BioMed Research International
Volume 2018 (2018), Article ID 3819714, 32 pages
https://doi.org/10.1155/2018/3819714

Review Article

Natural Antispasmodics: Source, Stereochemical Configuration, and Biological Activity

Edith Fabiola Martínez-Pérez,1,2 Zaida N. Juárez,³ Luis R. Hernández,² and Horacio Bach¹

¹Department of Medicine, Division of Infectious Diseases, University of British Columbia, 2660 Oak Street, Vancouver, BC, Canada V6H 3Z6
²Departamento de Ciencias Químico-Biológicas, Universidad de las Américas Puebla, Ex Hacienda Sta. Catarina Mártir S/N, 72810 San Andrés Cholula, PUE, Mexico
³Ingeniería en Biotecnología, Facultad de Biotecnología, Decanato de Ciencias Biológicas, Universidad Popular Autónoma del Estado de Puebla, 21 Sur No. 1103, Barrio Santiago, 72410 Puebla, PUE, Mexico

Correspondence should be addressed to Luis R. Hernández; luisr.hernandez@udlap.mx and Horacio Bach; hbach@mail.ubc.ca

Received 24 July 2018; Accepted 28 August 2018; Published 8 October 2018

Academic Editor: Juergen Buenger

Copyright © 2018 Edith Fabiola Martínez-Pérez et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Natural products with antispasmodic activity have been used in traditional medicine to alleviate different illnesses since the remote past. We searched the literature and compiled the antispasmodic activity of 248 natural compounds isolated from terrestrial plants. In this review, we summarized all the natural products reported with antispasmodic activity until the end of 2017. We also provided chemical information about their extraction as well as the model used to test their activities. Results showed that members of the Lamiaceae and Asteraceae families had the highest number of isolated compounds with antispasmodic activity. Moreover, monoterpenoids, flavonoids, triterpenes, and alkaloids were the chemical groups with the highest number of antispasmodic compounds. Lastly, a structural comparison of natural versus synthetic compounds was discussed.

1. Introduction

Antispasmodic compounds are currently used to reduce anxiety, emotional and musculoskeletal tension, and irritability. Although most of the available antispasmodic compounds are synthetic or semisynthetic, traditional uses of this group of compounds are still popular.

We collected information about natural compounds with antispasmodic activity isolated from terrestrial plants. We searched the databases of Google Scholar, PubMed, and SciFinder and compiled the information about 248 compounds published until December 2017. This review focuses on the antispasmodic activity of isolated compounds and activities from extracts without further purification are not discussed.

2. The Neurons

Nerve cells or neurons are responsible for receiving, conducting, and transmitting signals. A neuron consists of a nucleated body, a long thin extension called an axon, and several dendrites or prolongations extended from the cell body. Axons conduct signals from the nucleated body towards distant targets, while dendrites provide an enlarged surface area to receive signals from the axons of other neurons.

Signal transmission through axons is driven by a change in the electrical potential across the plasma membrane of neurons. This plasma membrane contains voltage-gated cation channels, which are responsible for generation of action potentials. An action potential is triggered by a depolarization of the plasma membrane or a shift to a less negative value.

In nerve and skeletal muscle cells, a stimulus can cause sufficient depolarization to open voltage-gated Na⁺ channels allowing the entrance of Na⁺ into the cell. This influx of Na⁺ depolarizes the membrane further causing the opening of more Na⁺ channels. To avoid a permanent influx, Na⁺ channels are able to reclose rapidly even when the membrane is still depolarized. This function is based on the presence of voltage-gated K⁺ channels, which are responsible for K⁺ efflux equilibrating the membrane potential even before the total inactivation of Na⁺ channels. In some cases, the action potential in some muscles depends on voltage-gated Ca²⁺ channels.

2.1. Transmission of Signals

The transmission of signals occurs mainly between neurons or from neurons to skeletal muscles, which are the final acceptors of electrical signals, causing a muscular contraction.

2.1.1. Signal Transmission between Neurons

Neuronal signals are transmitted between neurons at specialized sites of contact known as synapses. Neurons are separated by a synaptic cleft where a release of a neurotransmitter occurs. This neurotransmitter is stored in vesicles and is released by exocytosis. Upon triggering, the neurotransmitter is released into the cleft provoking an electrical change in the postsynaptic cell by binding to the transmitter-gated ion channels. To avoid a continuous electrical change and to ensure both spatial and temporal precision of signal transmission, the neurotransmitter is rapidly removed from the cleft either by specific enzymes in the synaptic cleft or by reuptake mediated by neurotransmitter carrier proteins [1].

Neurotransmitters can also open cation channels causing an influx of Na⁺ and then called excitatory neurotransmitters (e.g., acetylcholine, glutamate, and serotonin) or produce an opening of Cl⁻ channels and then inhibiting the signal transmission by maintaining the postsynaptic membrane polarization [e.g., γ-aminobutyric acid (GABA) and glycine].

2.1.2. Neuromuscular Signal Transmission

The transmission of electrical signals to muscles involves five sequential and orchestrated steps: (i) nerve electric signal reaches the nerve terminal, (ii) it depolarizes the plasma membrane of the terminal, (iii) voltage-gated Ca²⁺ channels opens causing an increase in Ca²⁺ concentration in the neuron cytosol, and (iv) release of acetylcholine into the synaptic cleft is triggered. Acetylcholine binds to acetylcholine receptors in the muscle plasma membrane opening Na⁺ channels and provoking a membrane depolarization. This depolarization enhances the opening of more Na⁺ channels causing a self-propagating depolarization. The generalized depolarization of the muscle plasma membrane activates Ca²⁺ channels in specialized regions on the membrane causing Ca²⁺ release from the sarcoplasmic reticulum (Ca²⁺ storage) into the cytosol.

As a consequence of an increase in the Ca²⁺ concentration, myofibrils in the muscle cell contract. The increase of Ca²⁺ in the cytosol is transient because Ca²⁺ is rapidly pumped back into the sarcoplasmic reticulum causing a relaxation of the myofibrils. This process is very fast and Ca²⁺ concentration at resting levels is restored within 30 milliseconds [2].

3. Receptors

The autonomic nerve system controls and monitors the internal environment of the body. The input of its activity is provided by neurons that are associated with specific sensory receptors located in the blood vessels, muscles, and visceral organs (Table 1). According to the neurotransmitter secreted, these neurons are classified as adrenergic or cholinergic. The adrenergic neurons secrete the neurotransmitter noradrenalin termed also norepinephrine. Adrenergic receptors include the types α and β, which are further categorized as α₁, α₂, β₁, β₂, and β₃. On the other hand, cholinergic neurons secrete acetylcholine, which induces a postsynaptic event. There are two types of cholinergic receptors, the nicotinic receptor (abundant at the neuromuscular junction) and the muscarinic receptor (abundant on smooth and cardiac muscles and glands).

Table 1: Receptors targeted by neurotransmitters in the body.

Receptor
Targeted by

Adrenergic
Epinephrine (adrenaline)

Norepinephrine (noradrenaline)

Dopaminergic
Dopamine

Cholinergic
Acetylcholine

GABAergic
GABA

Glutaminergic
Glutamate

Histaminergic
Histamine

Serotonergic
Serotonin

Glycinergic
Glycine

Opioid
Dynorphin

Enkephalin

Endorphin

Endomorphin

Nociceptin

There are several agonists (neurotransmitters, hormones, and others) able to bind to specific receptors and activate the contraction of smooth muscle. Upon binding the agonist to the receptor, the mechanism of contraction is based on an increase of phospholipase C. This enzyme hydrolyzes phosphatidylinositol 4,5-bisphosphate located on the membrane, producing two powerful secondary messengers termed diacylglycerol (DG) and inositol 1,4,5 triphosphate (IP3). IP3 binds to specific receptors in the sarcoplasmic reticulum, causing release of Ca²⁺ within the muscle. DG together with Ca²⁺ activates the protein kinase C (PKC), which phosphorylates specific proteins. In most smooth muscles, the contraction process commences when PKC phosphorylates Ca²⁺ channels or other proteins that regulate the cyclic process. For instance, Ca²⁺ binds to calmodulin (a multifunctional intermediate calcium-binding messenger protein), triggering the activation of the myosin light chain (MLC) kinase, which phosphorylates the light chain of myosin and together with actin carries out the process of initiating the shortening of the smooth muscle cell [147]. However, the elevation of the intracellular concentration of Ca²⁺ is transient, and the contractile response is maintained by a mechanism sensitized by Ca²⁺ modulated by the inhibition of myosin phosphatase activity by Rho kinase. This mechanism sensitized to Ca²⁺ is initiated at the same time that phospholipase C is activated and involves the activation of the small RhoA protein bound to guanosine triphosphate (GTP). Above activation, RhoA increases the activity of Rho kinase, leading to the inhibition of myosin phosphatase. This promotes the contractile state, since the myosin light chain cannot be dephosphorylated [147].

Relaxation of smooth muscle occurs as a result of either removing the contractile stimuli or by the direct action of a substance that stimulates the inhibition of the contractile mechanism. In any circumstance, the relaxation process requires a decrease in the intracellular Ca²⁺ concentration and an increase in the activity of the MLC phosphatase. The sarcoplasmic reticulum and plasma membrane remove Ca²⁺ from the cytosol. Na⁺/Ca²⁺ channels are located on the plasma membrane and help to reduce the intracellular concentration of Ca²⁺. During relaxation, other contributors that restrict the Ca²⁺ entry into the cell are the voltage-operated channels and Ca²⁺ receptors in the plasma membrane, which remain closed [147].

4. Spasmodic Compounds

The historical antecedents date from the year 1504 when South American natives inhabiting the basins of the high Amazon and the Orinoco prepared a mixture of alkaloids termed curare. This substance was placed in the tips of arrows in order to hunt (prey paralyzing) and fight in wars. Curare produces muscle weakness, paralysis, respiratory failure, and death [148]. In 1800, Alexander von Humboldt, identified that curare was made from the extracts of the species Chondrodendron tomentosum and Strychnos toxifera.

In 1935, the French physiologist Claude Bernard managed to isolate the alkaloid d-tubocurarine from the curare [149]; and one year later, it was elucidated that this compound had the ability to inhibit acetylcholine, blocking the transmission of nerve impulses to the muscles [150]. Lastly, new benzylisoquinoline alkaloids were isolated from curare by Galeffi et al. in 1977 [151, 152].

In 1822, the pharmacist Rudolph Brandes obtained an impure alkaloid from Atropa belladonna (Solanaceae), which after purification was named atropine. Interestingly, atropine was not produced as a natural compound from the plant and it was a derivative generated from the alkaloid hyoscyamine during the process of purification [153]. It is important to note that atropine has been naturally found in small quantities in other members of the Solanaceae family such as Datura stramonium, Duboisia myoporoides, and Scopolia japonica [154–156].

The use of the plant Papaver somniferum (opium poppy) (Papaveraceae) dates back to about 4000 BC. At present the plant is only used to extract a base material for the manufacture of other alkaloids, such as noscapine and codeine, both discovered by the French pharmacist Pierre-Jean Robiquet in 1831 and 1832, respectively [157]. In 1848, papaverine was another substance extracted from the same plant by the German chemist Georg Merck [158], which is rarely used today because of the high doses needed (approximately 6 to 12 mg). However, it is still used as a control in experimental models with the purpose of studying antispasmodic activity of plant extracts.

In the century, extracts and powders derived from A. belladonna were widely used as antispasmodics, but from the 1950s these preparations were displaced by synthetic and semisynthetic anticholinergic compounds in order to obtain a better response [159], such as the case of methocarbamol and guaifenesin. On the other hand, a series of compounds such as dantrolene, glutethimide, methaqualone, chlormezanone, metiprilone, and ethchlorvynol were introduced to replace the meprobamate, which had to be withdrawn from the market in 1960 due to problems resulting from use such as abstinence, addictions, and overdoses.

In 1962, the Swiss chemist Heinrich Keberle synthesized baclofen, which can be obtained by reacting glutarimide with an alkaline solution [160]. Glutarimide can also be found in plants such as Croton cuneatus and C. membranaceus (Euphorbiaceae) [161, 162].

The arrival of the quaternary compounds of nitrogen reinforce their peripheral anticholinergic activity offering also the advantages of being poorly absorbed in the gastrointestinal tract, producing a more powerful and longer lasting sedative effect unlike atropine [1]. For example, ipratropium bromide was developed by the German company Boehringer Ingelheim in 1976 and used to treat asthma. This compound was obtained by reacting atropine with isopropyl bromide [163]. Another quaternary compound was the n-butylhyoscine bromide, which is possible to obtain by the organic synthesis of scopolamine and the cimetropium bromide found in the A. belladonna [164]. Although at present the preparations of plant mixtures are no longer used for therapeutic purposes, these compounds formed a part of and served as the basis for modern pharmacology for their applicability as antispasmodics and anesthetics.

Spasms are involuntary contractions of the muscles, which are normally accompanied by pain and interfere with the free and effective muscular voluntary activity. Muscle spasm can originate from multiple medical conditions and is often associated with spinal injury, multiple sclerosis, and stroke.

Spasticity and rigidity are caused by a disinhibition of spinal motor mechanisms. There are several scenarios where a muscle can produce a spasm: (i) unstable depolarization of motor axons; (ii) muscular contractions persist even if the innervation of muscle is normal and despite attempts of relaxation (myotonia); (iii) after one or a series of contractions, the muscle can decontract slowly, as occurring in hypothyroidism; and (iv) muscles lack the energy to relax.

4.1. Distribution of Spasmodic Compound in Nature

Spasmodic compounds are widely distributed in nature (Table 2). Frequently, these compounds are found in animals that paralyze their preys or used for defense. Some examples include the venom of the black widow and tarantula spiders [11, 165] and the venom of snakes [166]. Plants also produce spasmodic metabolites, such as strychnine, an alkaloid obtained from the tree Strychnos nux-vomica (Loganiaceae). Furthermore, microorganisms synthesize spasmodic compounds such as the neurotoxins tetanospasmin and botulinum toxin from the Gram-positive bacteria Clostridium tetani and C. botulinum, respectively. These toxins produce a toxic disorder, which is characterized by persistent spasms of skeletal muscles on spinal neurons similar to strychnine.

Table 2: Representative organisms producing spasmodic compounds.

Compound
Organism
Symptoms
Mechanism
Reference

Bacterial

Botulinum toxin
Clostridium botulinum
Muscular relaxation
Secretion of acetylcholine into synapses is blocked
[3]

Tetanospasmin
Clostridium tetani
Muscular spasm
Inhibits the binding of GABA and glycine
[4]

Marine

Nematocyst venom extract
Sea anemones
Nausea, vomiting, muscle cramp, severe pain, paralysis
Delay in the voltage-dependent Na⁺ channels inactivation
[5]

Nematocyst venom extract
Chironex fleckeri (Cnidaria)
Contraction of arterial smooth muscle
Increase of cytosolic Ca²⁺ concentration
[6]

Ciguatoxin
Gambierdiscus toxicus (Dinoflagellate)
Nausea, vomiting, abdominal pain, intestinal spasm
Interact with voltage-gated increasing the Na⁺ permeability and Ca²⁺ homeostasis
[7]

Chordata
Plotosus lineatus (Catfish)
Violent pain, shock, spasm
Increase of the vascular permeability in peritoneum
[8]

Terrestrial

Ergotamine
Claviceps purpurea (fungus)
Seizure, spasms psychosis, nausea, vomiting
Agonist of several neurotransmitter receptors
[9]

α-Latrotoxin
Latrodectus tredecimguttatus (black widow spider)
Facial flushing, hypertension, muscle spasm, tachycardia
Causes Ca²⁺-dependent and -independent release of neurotransmitters
[10]

Vanillo-toxin, hanatoxin, huwentoxin
Tarantula species
Severe pain, cramps, erythema, swelling, tachycardia
Unrevealed
[11–14]

β-Neurotoxin
Mesobuthus martensii (scorpion)
Increases muscular contraction, spasm, convulsion
Modulates Ca²⁺ channels
[15]

Crotoxin
Crotalus durissus terrificus (rattlesnake)
Severe pain, drooping eyelids, low blood pressure, muscle weakness
Blocks the cholinergic post-synaptic response
[16]

4.2. Mechanisms of Antispasmodic Activity of Natural Products

Antispasmodic compounds exert their activity in different ways, such as antispasmodic activity through inhibition of the response to the neurotransmitters 5-hydroxytryptamine (5-HT) or serotonin and acetylcholine. However, other authors attribute the antispasmodic effect to (i) capsaicin-sensitive neurons, (ii) the participation of vanilloid receptors [167], (iii) the activation of K⁺ ATP channels, (iv) the blockade of Na⁺ channels and muscarinic receptors, (v) the reduction of extracellular Ca²⁺, or (vi) the blockade of Ca²⁺ channels [22, 168, 169]. The above is merely a reflection of the ambiguity of the studies showing the mechanisms of action of the antispasmodic compounds [36]. For example, the hydroalcoholic extract of Marrubium vulgare showed antispasmodic effect, having the ability to inhibit the neurotransmitters acetylcholine, bradykinin, prostaglandin E2, histamine, and oxytocin [170], whereas a dual effect of antidiarrheal and laxative activities was reported in Fumaria parviflora [171].

5. Methods Used to Evaluate Antispasmodic Compounds

5.1. Gastrointestinal Model

The small intestine is characterized by its large surface area as a result of its circular folds, villi, and microvilli. It is the longest part of the GI system (approximately 5 meters) and comprises about 5% of its initial length, which corresponds to the duodenum (characterized by the absence of the mesentery) and then the jejunum (around 40% of the intestinal length), ending with the ileum. It is the organ of absorption of nutrients and digestion in organisms. These functions are carried out mainly in the duodenum and jejunum.

The main types of bowel movement are the segmentation and peristaltism. The segmentation is most frequent in the small intestine and consists of contractions of the circular muscle layer in very close areas. Contractions last for 11-12 and 8-9 contractions per min in the duodenum and ileum, respectively. When this segmentation is rhythmic, the contractions are alternated with relaxation. This type of movement results in a mixed effect of the chyme (acidic fluid that passes from the stomach to the small intestine) with the digestive secretions, allowing an optimal contact with the intestinal mucosa. In the case of peristalsis, contractions of successive sections of the circular smooth muscle cause the movement of the intestinal contents in anterograde form. The short peristaltic movement also takes place in the small intestine, but less frequently than the segmentation movements. Peristaltic waves rarely cross more than 10 cm of intestine and, due to the low frequency of propulsion of the chyme, it is in this zone where digestion and absorption are preferably carried out. Peristalsis is regulated mainly by the nervous action of the myenteric plexus (major nerve supply to the gastrointestinal tract that controls GI tract motility) in the intestinal wall.

The diversity of experimental models used for the testing of antispasmodic compounds is large. These models mainly use isolated organs or live animals. Once the organ is extracted from the animal, the intestinal motility is assessed with the administration of a substance. The use of extracted organs can be sustained for hours when placed in a physiological solution, such as Ringer, Jalon, Tyrode, and Krebs [172].

The most used organs to perform the studies are guinea pig ileum, duodenum, heart, trachea, and jejunum. The same organs can be also extracted from rabbit, mouse, rat, and hamster (Table 3). The preparation of ileum is preferred because it evaluates the spasmolytic activity. However, although the jejunum contracts spontaneously, it allows evaluating the spasmolytic activity directly and without the use of an agonist [173].

Table 3: Natural products with antispasmodic activity isolated from terrestrial plants.

Compound name
Species (Family)
Preparation (Solvent)
Model tested
Source
Reference

Monoterpenoids

1 Myrcene, β-myrcene
Plectranthus barbatus (Lamiaceae)
Leaf (MeOH)
ACh, BaCl₂, KCl in guinea pig ileum
EO
[17]

2 Citral B, β-citral, Neral
Aloysia triphylla (Verbenaceae)
Leaf (Hexane)
Carbachol, KCl, O, PGF (2α) in rat uterus
IC
[18]

Cymbopogon citratus (Poaceae)
Leaf (MeOH 70%)
ACh, KCl in rabbit ileum
IC
[19]

Melissa officinalis (Lamiaceae)
Aerial part (EtOH 70%)
ACh, KCl in rat ileum
EO
[20]

3 Geranyl formate
Anthemis mauritiana (Compositae)
Flower (Distillation)
Ca²⁺, carbachol, KCl in rabbit and rat jejunum
EO
[21]

4 Geranyl acetate
Nepeta cataria (Lamiaceae)
Leaf (Aqueous)
Carbachol, KCl in guinea pig trachea and rabbit jejunum
EO
[22]

5 Geraniol
Rosa damascene (Rosaceae)
Flower (hydrodistillation)
ACh, KCl, electrical field stimulation in rat ileum
IC
[23]

6 Citronellol
Rosa damascene (Rosaceae)
Flower (hydrodistillation)
ACh, KCl, electrical field stimulation in rat ileum
IC
[23]

7 (±)--Phellandrene
Zingiber officinale (Zingiberaceae)
Rhizome (MeOH)
Serotonin in rat ileum
EO
[24]

8 (±)--Phellandrene
Croton sonderianus (Euphorbiaceae)
Leaf (Distillation)
ACh, KCl in rat tracheal smooth muscle
EO
[25]

9 Terpinolene
Zingiber officinale (Zingiberaceae)
Rhizome (MeOH)
Serotonin in rat ileum
EO
[24]

10 D-(+)-Limonene
Zingiber roseum (Zingiberaceae)
Fresh seeds (Hydrodistilled with diethyl ether)
Carbachol, KCl in rat duodenal smooth muscle
EO
[26]

Mentha x villosa (Lamiaceae)
Leaf infusion (MeOH)
KCl in guinea pig ileum
IC
[27]

Dracocephalum kotschyi (Lamiaceae)
Aerial part (Hydrodistillation)
ACh, electrical field stimulation, KCl in rat ileum
EO
[28]

11  -Terpinene
Acalypha phleoides (Euphorbiaceae)
Aerial part infusion MeOH-CHCl₃ (1:1)
ACh, BaCl₂, H, S in guinea pig ileum and rabbit jejunum
IC
[29]

12 Thymoquinone
Nigella sativa (Ranunculaceae)
Seed infusion (Aqueous)
BaCl₂, carbachol, leukotriene in rat trachea
IC
[30]

13 (R)-(+)-Pulegone
Calamintha glandulosa (Lamiaceae)
Aerial parts infusion (Diethyl ether)
KCl in rat ileum
IC
[31]

Mentha x villosa (Lamiaceae)
Leaf infusion (MeOH)
KCl in guinea pig ileum
IC
[27]

14 (-)-Menthol
Mentha piperita (Lamiaceae)
Leaf and flower infusion (EtOH)
S in rat ileum
IC
[32]

15 dl--Terpineol
Casimiroa pringlei (Rutaceae)
Aerial part infusion (Ethylic ether)
KCl in rat uterine smooth muscle
IC
[33]

Zingiber roseum (Zingiberaceae)
Fresh seeds (Hydrodistilled with diethyl ether)
Carbachol, KCl in rat duodenal smooth muscle
EO
[26]

Dracocephalum kotschyi (Lamiaceae)
Aerial part (Hydrodistillation)
ACh, electrical field stimulation, KCl in rat ileum
EO
[28]

16 (-)-Piperitone
Casimiroa pringlei (Rutaceae)
Aerial part infusion (Ethylic ether)
KCl in rat uterine smooth muscle
IC
[33]

17 (+)-Rotundifolone
Mentha x villosa (Lamiaceae)
Leaf infusion (MeOH)
KCl in guinea pig ileum
IC
[27]

18 ()-(-)-Carvone
Mentha x villosa (Lamiaceae)
Leaf infusion (MeOH)
KCl in guinea pig ileum
IC
[27]

19 (R,R,R)-Carvone-1,2-oxide)
Mentha x villosa (Lamiaceae)
Leaf infusion (MeOH)
KCl in guinea pig ileum
IC
[27]

20 (S)-(+)-Carvone
Mentha x villosa (Lamiaceae)
Leaf infusion (MeOH)
KCl in guinea pig ileum
IC
[27]

21 1,8-Cineole
Ocimum gratissimum (Lamiaceae)
Leaf infusion (MeOH)
ACh, KCl in guinea pig ileum
IC
[34]

Nepeta cataria (Lamiaceae)
Leaf infusion (Aqueous)
Carbachol, KCl in guinea pig trachea and rabbit jejunum
EO
[22]

Casimiroa pringlei (Rutaceae)
Aerial part infusion (Ethylic ether)
KCl in rat uterine smooth muscle
IC
[33]

22  p-Cymene
Lippia graveolens (Verbenaceae)
Leaf infusion (Distillation)
Carbachol, H in guinea pig ileum
IC
[35]

Zingiber roseum (Zingiberaceae)
Fresh seeds (Hydrodistilled with diethyl ether)
Carbachol, KCl in rat duodenal smooth muscle
EO
[26]

Poliomintha longiflora (Lamiaceae)
Leaves stem infusion (Distillation)
Carbachol, H in guinea pig ileum
IC
[35]

23 Carvacrol
Origanum acutidens (Lamiaceae)
Leaf, stem and flower infusion (MeOH)
Spontaneous contraction in rat ileum
EO
[36]

Thymus vulgaris (Lamiaceae)
Whole plants (Ethanol)
ACh, BaCl2, KCl in rat trachea and ileum
IC
[37]

24 Thymol
Acalypha phleoides (Euphorbiaceae)
Aerial part infusion [MeOH-CHCl₃ (1:1)]
ACh, BaCl₂, H, KCl, S in guinea pig ileum and rabbit jejunum
IC
[29]

Thymus vulgaris (Lamiaceae)
Whole plants (Ethanol)
ACh, BaCl2, KCl in rat trachea and ileum
IC
[37]

25 Thujane or Sabinane
Anthemis mauritiana (Asteraceae)
Flower infusion (Aqueous)
Carbachol, KCl in rabbit jejunal smooth muscle
EO
[21]

26 (±)-Camphor
Acalypha phleoides (Euphorbiaceae)
Aerial part infusion [MeOH-CHCl₃ (1:1)]
ACh, BaCl₂, H, KCl, S in guinea pig ileum and rabbit jejunum
IC
[29]

Lippia dulcis (Verbenaceae)
Leaf infusion (Steam distillation)
Carbachol, H in porcine bronchi
EO
[38]

27 (+)--Pinene
Anthemis mauritiana (Asteraceae)
Flower infusion (Aqueous)
Carbachol, KCl in rabbit jejunal smooth muscle
EO
[21]

Nepeta cataria (Lamiaceae)
Leaf infusion (Aqueous)
Carbachol, KCl in guinea pig trachea and rabbit jejunum
EO
[22]

Plectranthus barbatus (Lamiaceae)
Leaf infusion (MeOH)
ACh, BaCl₂, H, KCl in guinea pig ileum
EO
[17]

28 (-)--Pinene
Dissotis rotundifolia (Melastomataceae)
Leaf infusion (EtOH)
Carbachol in mouse intestinal motility
E
[39]

Eucalyptus tereticornis (Myrtaceae)
Commercial
ACh, KCl in rat trachea
EO
[40]

Zingiber roseum (Zingiberaceae)
Fresh seeds (Hydrodistilled with diethyl ether)
Carbachol, KCl in rat duodenal smooth muscle
EO
[26]

29 (+)--Pinene
Ferula gummosa (Apiaceae)
Resin infusion (Hydroalcoholic, ether, MeOH)
ACh, KCl in rat ileum
IC
[41]

Zingiber officinale (Zingiberaceae)
Rhizome infusion (MeOH)
S in rat ileum
EO
[24]

Zingiber roseum (Zingiberaceae)
Fresh seeds (Hydrodistilled with diethyl ether)
Carbachol, KCl in rat duodenal smooth muscle
EO
[26]

30 Cantleyine
Strychnos trinervis (Loganiaceae)
Root bark (EtOAc)
Carbachol, H, KCl in guinea pig trachea
IC
[42]

31 Penstemonoside
Parentucellia latifolia (Scrophulariaceae)
Whole plant infusion (Butanol)
ACh, CaCl₂, KCl in rat uterus
IC
[43]

32 Aucubine or aucuboside
Parentucellia latifolia (Scrophulariaceae)
Whole plant infusion (Butanol)
ACh, CaCl₂, KCl in rat uterus
IC
[43]

33 2′-O-Acetyldihydropenstemide
Viburnum prunifolium (Caprifoliaceae)
Root and stem bark infusion (MeOH)
Carbachol in rabbit jejunum and guinea pig trachea
E
[44]

34 2′-O-trans-p-Coumaroyl-dihydropenstemide
Viburnum prunifolium (Caprifoliaceae)
Root and stem bark infusion (MeOH)
Carbachol in rabbit jejunum and guinea pig trachea
E
[44]

35 2′-O-Acetylpatrinoside
Viburnum prunifolium (Caprifoliaceae)
Root and stem bark infusion (MeOH)
Carbachol in rabbit jejunum and guinea pig trachea
E
[44]

36 Patrinoside
Viburnum prunifolium (Caprifoliaceae)
Root and stem bark infusion (MeOH)
Carbachol in rabbit jejunum and guinea pig trachea
E
[44]

37 Valtriate or Valepotriate
Valeriana procera (Valerianeaceae)
Root infusion (EtOH)
BaCl₂, carbachol, KCl in guinea pig ileum and stomach
IC
[45]

38 Isovaltrate or Isovaltratum
Valeriana procera (Valerianeaceae)
Root infusion (EtOH)
BaCl₂, carbachol, KCl in guinea pig ileum and stomach
IC
[45]

39 Epoxygaertneroside
Morinda morindoides (Rubiaceae)
Leaf infusion (Aqueous)
ACh, KCl in guinea pig ileum
IC
[46]

40 Gaertneroside
Morinda morindoides (Rubiaceae)
Leaf infusion (Aqueous)
ACh, KCl in guinea pig ileum
IC
[46]

41 Catalpinoside or Catapol
Parentucellia latifolia (Scrophulariaceae)
Whole plant infusion (Butanol)
ACh, CaCl₂, KCl in rat uterus
IC
[43]

Sesquiterpenes

43 (±)-Hernandulcin
Lippia dulcis (Verbenaceae)
Leaf infusion (Steam distillation)
Carbachol, H in porcine bronchi
EO
[38]

43 Humulene or α-Caryophyllene
Nepeta cataria (Lamiaceae)
Leaf infusion (Aqueous)
Carbachol, KCl, in guinea pig trachea and rabbit jejunum
EO
[22]

44β-Caryophyllene epoxide
Conyza filaginoides (Asteraceae)
Leaf infusion [CHCl₃:MeOH (1:1)]
Spontaneous contraction in rat ileum
IC
[47]

Croton sonderianus (Euphorbiaceae)
Leaf infusion (Steam distillation)
ACh, KCl in rat tracheal smooth muscle
EO
[25]

45β-Caryophyllene
Croton sonderianus (Euphorbiaceae)
Leaf infusion (Steam distillation)
ACh, KCl in rat tracheal smooth muscle
EO
[25]

Conyza filaginoides (Asteraceae)
Leaf infusion [CHCl₃:MeOH (1:1)]
Spontaneous contraction in rat ileum
IC
[47]

Plectranthus barbatus (Lamiaceae)
Leaf infusion (MeOH)
ACh, BaCl₂, H, KCl in guinea pig ileum
EO
[17]

Pterodon polygalaeflorus (Fabaceae)
Seed (Steam distillation)
ACh, KCl in rat ileum smooth muscle
IC
[48]

46 Bicyclogermacrene or Lepidozene
Croton sonderianus (Euphorbiaceae)
Leaf infusion (Steam distillation)
ACh, KCl in rat tracheal smooth muscle
EO
[25]

47 (+)-Capsidiol
Nicotiana silvestri (Solanaceae)
Leaf infusion (EtOAc)
ACh, BaCl₂, bradykinin, carbachol in guinea pig ileum and trachea
IC
[49]

48 S-Petasin
Petasites formosanus (Compositae)
Aerial parts (EtOH)
CaCl₂, carbachol, H, KCl in guinea pig trachea
IC
[50]

49 (+)-Isopetasin
Petasites formosanus (Compositae)
Aerial parts (EtOH)
CaCl₂, carbachol, H, KCl in guinea pig trachea
IC
[50]

50 Valeranone o Jatamansone
Valeriana procera (Valerianeaceae)
Root infusion (EtOH)
BaCl₂, carbachol, KCl in guinea pig ileum and stomach
IC
[45]

51 Chamazulene
Matricaria recutita (Asteraceae)
Plant infusion (Aqueous)
Human platelet
E
[51]

52 Spathulenol
Croton sonderianus (Euphorbiaceae)
Leaf infusion (Steam distillation)
ACh, KCl in rat tracheal smooth muscle
EO
[25]

Lepechinia caulescens (Lamiaceae)
Leaf infusion (Hexane)
KCl in rat uterus
IC
[52]

53 Cynaropicrin
Cynara scolymus (Asteraceae)
Leaf and flower infusion (MeOH 70%)
ACh in guinea pig ileum
IC
[53]

54 Cedrenol
Anthemis mauritiana (Asteraceae)
Flower infusion (Aqueous)
Carbachol, KCl in rabbit jejunal smooth muscle
EO
[21]

55 (+)-Bakkenolide A
Hertia cheirifolia (Asteraceae)
Aerial parts (MeOH)
ACh, BaCl₂ in rat duodenum
IC
[54]

56 Himachalol
Cedrus deodara (Pinaceae)
Wood infusion
ACh, BaCl₂, H, nicotine, S in guinea pig ileum and seminal vesicle, rabbit jejunum and rat uterus
IC
[55]

57 (E)-Damascenone
Ipomoea pes-caprae (Convolvulaceae)
Leaf infusion (Aqueous)
H in guinea pig ileal smooth muscle
IC
[56]

58 (-)-Isogermacrene D
Artemisia vulgaris (Compositae)
Stem and leaf infusion (Aqueous)
guinea pig ileum

[57]

59 Ezoalantonin
Artemisia vulgaris (Compositae)
Leaf (CHCl₃)
H, PMA, S in guinea pig ileum and trachea
IC
[57]

60 Costunolide
Radix aucklandiae (Asteraceae)
Rhizome (MeOH)
ACh, KCl, S in rat jejunum
IC
[58]

61 Dehydrocostuslactone
Radix aucklandiae (Asteraceae)
Rhizome (MeOH)
ACh, KCl, S in rat jejunum
IC
[58]

Diterpenes

62 E-Phytol
Ipomoea pes-caprae (Convolvulaceae)
Leaf infusion (Aqueous)
H in guinea pig ileal smooth muscle
IC
[56]

63 3α-Angeloyloxy-2α-hydroxy-13,14Z-dehydrocativic acid
Brickellia paniculata (Compositae)
Leaf infusion (MeOH)
KCl in rat myometrial tissue
IC
[59]

64 15-Epicyllenin A
Marrubium globosum ssp. libanoticum (Lamiaceae)
Aerial part infusion (MeOH)
ACh in mouse ileum
IC
[60]

65 Cyllenin A
Marrubium globosum ssp. libanoticum (Lamiaceae)
Aerial part infusion (MeOH)
ACh in mouse ileum
IC
[60]

66 Marrulibacetal
Marrubium globosum ssp. libanoticum (Lamiaceae)
Aerial part infusion (MeOH)
ACh in mouse ileum
IC
[60]

67 (13R)-9α,13α-epoxylabda-6β(19),16(15)-diol dilactone
Marrubium globosum ssp. libanoticum (Lamiaceae)
Aerial part infusion (MeOH)
ACh in mouse ileum
IC
[60]

68 Marrubin
Marrubium vulgare (Lamiaceae)
Aerial parts (Aqueous)
KCl in rat aorta
IC
[61]

69 Marrubenol or Marrubiol
Marrubium vulgare (Lamiaceae)
Aerial parts (Aqueous)
KCl in rat aorta
IC
[61]

70 Marrulanic acid
Marrubium globosum ssp. libanoticum (Lamiaceae)
Aerial part infusion (MeOH)
ACh in mouse ileum
IC
[60]

71 Marrulactone
Marrubium globosum ssp. libanoticum (Lamiaceae)
Aerial part infusion (MeOH)
ACh in mouse ileum
IC
[60]

72 (+)-Dehydroabietic acid
Lepechinia caulescens (Lamiaceae)
Leaf infusion (Hexane)
KCl in rat uterus
IC
[52]

73 9β-Hydroxydehydroabietyl alcohol
Lepechinia caulescens (Lamiaceae)
Leaf infusion (Hexane)
KCl in rat uterus
IC
[52]

74 9α,13α-Epidioxyabiet-8(14)-en-18-oic acid methyl ester
Lepechinia caulescens (Lamiaceae)
Leaf infusion (Hexane)
KCl in rat uterus
IC
[52]

75 4-epi-Hyalic acid
Croton argyrophylloides (Euphorbiaceae)
Bark infusion (MeOH)
ACh, KCl in rat tracheal smooth muscle
IC
[62]

76 Pimaradienoic acid or Continentalic acid
Viguiera arenaria (Asteraceae)
Root infusion (CH₂Cl₂)
ACh, KCl in rat carotid artery
IC
[63]

77 8(14),15-Sandaracopimaradiene-7α,18-diol
Tetradenia riparia (Lamiaceae)
Leaf infusion (CHCl₃)
BaCl₂, H, methacholine in guinea pig ileum
IC
[64]

78 3,4-Secoisopimara-4(18),7,15-triene-3-oic acid
Salvia cinnabarina (Lamiaceae)
Aerial parts (EtOH)
ACh, BaCl₂, H in guinea pig ileum
IC
[65]

79 ent-Kaurenoic acid
Viguiera arenaria (Asteraceae)
Root infusion (CH₂Cl₂)
ACh, KCl in rat carotid artery
IC
[63]

Viguiera hypargyrea (Asteraceae)
Root infusion (Hexane)
Spontaneous contraction in guinea pig ileum
IC
[66]

80 Beyerenic acid or Monogynoic acid
Viguiera hypargyrea (Asteraceae)
Root infusion (Hexane)
Spontaneous contraction in guinea pig ileum
IC
[66]

81 ent-7α-Acetoxytrachyloban-18-oic acid
Xylopia langsdorfiana (Annonaceae)
Stem infusion (EtOH 95%)
BaCl₂, H, KCl in guinea pig ileum
IC
[67]

82 ent-7α -hydroxytrachyloban-18-oic acid
Xylopia langsdorfiana (Annonaceae)
Stem infusion (EtOH 95%)
BaCl₂, H, KCl in guinea pig ileum
IC
[67]

83 Phorbol 12-acetate-13-tiglate
Crotonis tiglium (Euphorbiaceae)
Fruit (MeOH)
Spontaneous contraction in rabbit jejunum
E
[68]

84 3,7,10,14,15-pentaacetyl-5-butanoyl-13,17-epoxy-8-myrsinene
Pycnocycla spinosa (Umbelliferae)
Aerial parts (MeOH)
KCl in rat illeum
IC
[69]

Triterpenoids

85 Agapanthagenin 3-O-β-D-glucopyranoside
Allium elburzense (Alliaceae)
Flower and bulb infusion (Hexane)
H in guinea pig ileum
IC
[70]

86 Agapanthagenin
Allium elburzense (Alliaceae)
Flower and bulb infusion (Hexane)
H in guinea pig ileum
IC
[70]

87β-sitosterol
Eucalyptus camaldulensis (Myrtaceae)
Leaf infusion (EtOAc)
KCl, spontaneous contraction in rabbit jejunum
IC
[71]

88 β-sitosterol 3-O-β-D-glucopyranoside
Eucalyptus camaldulensis (Myrtaceae)
Leaf infusion (EtOAc)
KCl, spontaneous contraction in rabbit jejunum
IC
[71]

89 α-Spinasteryl β-D-glucoside
Conyza filaginoides (Asteraceae)
Leaf infusion [CHCl₃:MeOH (1:1)]
Spontaneous contraction in rat ileum
IC
[47]

90 Tropeoside B1 and B2
Allium cepa(Alliaceae)
Bulbs [CHCl₃:MeOH (9:1)]
ACh, H in guinea pig ileum
IC
[72]

91 Tropeoside A1 and A2
Allium cepa(Alliaceae)
Bulbs [CHCl₃:MeOH (9:1)]
ACh, H in guinea pig ileum
IC
[72]

92 Elburzensoside A1 and A2
Allium elburzense (Alliaceae)
Flower and bulb infusion (Hexane)
H in guinea pig ileum
IC
[70]

93 Elburzensoside C1 and C2
Allium elburzense (Alliaceae)
Flower and bulb infusion (Hexane)
H in guinea pig ileum
IC
[70]

94 Galphimin A
Galphimia glauca (Malpighiaceae)
Leaf infusion (MeOH)
Electrical-induced contraction in guinea pig ileum
IC
[73]

95 Galphimin B
Galphimia glauca (Malpighiaceae)
Leaf infusion (MeOH)
Electrical-induced contraction in guinea pig ileum
IC
[73]

96 Galphimin C
Galphimia glauca (Malpighiaceae)
Leaf infusion (MeOH)
Electrical-induced contraction in guinea pig ileum
IC
[73]

97 Galphimin E
Galphimia glauca (Malpighiaceae)
Leaf infusion (MeOH)
Electrical-induced contraction in guinea pig ileum
IC
[73]

98 Galphimin F
Galphimia glauca (Malpighiaceae)
Leaf infusion (MeOH)
Electrical-induced contraction in guinea pig ileum
IC
[73]

99 Handianol
Herissanthia tiubae (Malvaceae)
Leaf infusion (EtOH)
Carbachol, H, KCl in guinea pig ileum and trachea, and rat aorta
IC
[74]

100 Cycloartanol
Herissanthia tiubae (Malvaceae)
Leaf infusion (EtOH)
Carbachol, H, KCl in guinea-pig ileum, trachea and rat aorta
IC
[74]

101 Taraxasteryl acetate
Brickellia veronicifolia (Asteraceae)
Aerial parts [CH₂Cl₂:MeOH (1:1)]
Gastrointestinal motility test in mouse
E
[75]

102 Pomolic acid or Benthamic acid or Randialic acid A
Licania pittieri (Rosaceae)
Leaf infusion (EtOH)
Carbachol, KCl in rat aorta
IC
[76]

103 Ursolic acid
Agastache mexicana (Lamiaceae)
Aerial part (MeOH)
ACh, KCl in guinea pig ileum
IC
[77]

104 Ehretiolide
Eucalyptus camaldulensis (Myrtaceae)
Leaf infusion (EtOAc)
KCl, spontaneous contraction in rabbit jejunum
IC
[78]

105 Ehretiolide acetate
Eucalyptus camaldulensis (Myrtaceae)
Leaf infusion (EtOAc)
KCl, spontaneous contraction in rabbit jejunum
IC
[78]

106 Camaldulin
Eucalyptus camaldulensis (Myrtaceae)
Leaf infusion (EtOAc)
KCl, spontaneous contraction in rabbit jejunum
IC
[71]

107 Zygophyloside N
Zygophyllum gaetulum (Zygophyllaceae)
Root infusion (MeOH)
Electrically-induced contractions of isolated guinea pig ileum
E
[79]

108 Erythrodiol
Conyza filaginoides (Asteraceae)
Leaf infusion [CHCl₃:MeOH (1:1)]
Spontaneous contraction in rat ileum
IC
[47]

109 3-β-tridecanoyloxy-28-hydroxyolean-12-ene
Conyza filaginoides (Asteraceae)
Leaf infusion [CHCl₃:MeOH (1:1)]
Spontaneous contraction in rat ileum
IC
[47]

110 3--Hydroxyolean-9(11),12-dien-28-oic acid
Eucalyptus camaldulensis (Myrtaceae)
Leaf infusion (EtOAc)
KCl, spontaneous contraction in rabbit jejunum
IC
[78]

111 4-epi-Hederagenin
Hedera helix (Araliaceae)
Leaf infusion (EtOH)
ACh in guinea pig ileum
IC
[80]

112 Hederacoside C
Hedera helix (Araliaceae)
Leaf infusion (EtOH)
ACh in guinea pig ileum
IC
[80]

113 Betulinic acid
Eucalyptus camaldulensis (Myrtaceae)
Leaf infusion (EtOAc)
KCl, spontaneous contraction in rabbit jejunum
IC
[78]

114 α-Amyrin acetate
Tylophora hirsuta (Asclepiadaceae)
Aerial parts (MeOH)
KCl in rabbit jejunum
IC
[81]

Phloroglucinol derivatives

115 Hyperforin
Hypericum perforatum (Hypericaceae)
Aerial parts (EtOH 70%)
KCl in rabbit jejunum
IC
[82]

116 Hypericin
Hypericum perforatum (Hypericaceae)
Aerial parts (EtOH 70%)
KCl in rabbit jejunum
IC
[82]

Coumarins

117 Scopoletin
Brunfelsia hopeana (Solanaceae)
Root infusion (EtOH)
Phenylephrine, KCl, PGF2, serotonin in rat aorta
IC
[83]

118 Todannone
Toddalia asiatica var. floribunda (Rutaceae)
Aerial parts (EtOH 95%)
ACh, BaCl₂, H, nicotine in guinea pig ileum
IC
[84]

119 (2S,3R)-2-[(3E)-4,8-dimethylnona-3,7-dien-1-yl]-2,3-dihydro-7-hydroxy-2,3-dimethylfuro[3,2c] coumarin
Ferula heuffelii (Apiaceae)
Underground part (CHCl₃)
ACh, KCl in rat ileum
IC
[85]

120 Osthole
Prangos ferulacea (Apiaceae)
Root (Acetone)
ACh, KCl, electric field stimulation in rat ileum
IC
[86]

121 Angelicin
Heracleum thomsoni (Apiaceae)
Aerial part infusion (EtOH)
ACh, BaCl₂, H, S in cat ureter, guinea pig bile duct and trachea, monkey gall bladder, rabbit jejunum, and rat uterus
IC
[87]

122 Glycycoumarin
Glycyrrhizae radix (Leguminosae)
Root infusion (Aqueous)
A23187, BaCl₂, carbachol, KCl in mouse jejunum
IC
[88]

Glycyrrhiza ularensis (Leguminosae)
Root infusion (Aqueous)
Carbachol in mouse jejunum
E
[89]

Chalcones

123 Davidigenin
Mascarenhasia arborescens (Apocynaceae)
Leaf and stem infusion (MeOH)
ACh, H in guinea pig and rat duodenum
IC
[90]

124 Isoliquiritigenin
Glycyrrhiza glabra (Leguminosae)
Root infusion (Aqueous)
ACh, KCl, O, spontaneous contraction in rat uterus
IC
[91]

Glycyrrhiza ularensis (Leguminosae)
Root infusion (Aqueous) (Aqueous)
BaCl₂, carbachol, KCl in mouse jejunum,ileum and rectum
IC
[92]

125 Licochalcone A
Glycyrrhiza inflata (Leguminosae)
Root infusion (Aqueous)
A23187, BaCl₂, carbachol, KCl in mouse jejunum
IC
[93]

Flavonoids

126 (-)-Pinostrobin
Conyza filaginoides (Asteraceae)
Leaf infusion [CHCl₃:MeOH (1:1)]
Spontaneous contraction in rat ileum
IC
[47]

127 (-)-(S)-Sakuranetin
Dodonaea viscosa (Sapindaceae)
Leaf infusion [CHCl₃:MeOH (1:1)]
ACh, BaCl₂, H in rat uterus
IC
[94]

128 (±)-Sternbin
Artemisia monosperma (Compositae)
Aerial part (EtOH)
ACh, O in rat ileum, pulmonary artery, urinary bladder, trachea, and uterus
IC
[95]

129 Ouratea catechin
Maytenus rigida (Celastraceae)
Stem bark (EtOH)
BaCl₂, carbachol, KCl, H in guinea pig ileum
IC
[96]

130 Apegenin
Achillea millefolium (Asteraceae)
Whole plant infusion (MeOH 40%)
ACh, CaCl₂, H, PE, S in rat ileum
IC
[97]

131 Buddleoflavonol or Linarigenin
Agastache mexicana (Lamiaceae)
Aerial part (MeOH)
ACh, KCl in guinea pig ileum
IC
[77]

132 Luteolin
Achillea millefolium (Asteraceae)
Whole plant infusion (MeOH 40%)
ACh, CaCl₂, H, PE, S in rat ileum
IC
[97]

Artemisia copa (Compositae)
Aerial parts (Aqueous)
KCl, PE, S in rat aorta
E
[98]

Plantago lanceolata (Plantaginaceae)
Aerial part (EtOH)
ACh, BaCl₂, H, KCl in guinea pig ileum and trachea
IC
[99]

Thymus vulgaris (Lamiaceae)
Leaf and flower (EtOH)
ACh, BaCl₂, carbachol, H in guinea pig ileum and trachea, and rat vas deferens
IC
[100]

133 Scutellarein 6-β-D-glucoside (isovitexin)
Aloysia citridora (Verbenaceae)
Leaf infusion (Aqueous)
ACh, CaCl₂, KCl in rat duodenum
IC
[101]

134 Vitexin
Aloysia citridora (Verbenaceae)
Leaf infusion (Aqueous)
ACh, CaCl₂, KCl in rat duodenum
IC
[101]

Aspalathus linearis (Fabaceae)
Commercial (Aqueous)
KCl in rabbit jejunum
IC
[102]

135 Xanthomycrol
Brickellia paniculata (Compositae)
Leaf infusion (MeOH)
KCl, O in rat uterus
IC
[59]

136 Demethoxycentaureidin
Piptadenia stipulacea (Leguminosae)
Aerial parts, (CHCl₃)
Carbachol, H, O, in guinea pig ileum and trachea, rat aorta and uterus
IC
[103]

137 Gnaphaliin B
Gnaphalium liebmannii (Asteraceae)
Aerial parts (Hexane)
ACh, carbachol in guinea pig trachea
IC
[104]

138 Kaempferol or Kaempherol
Hedera helix (Araliaceae)
Aerial parts (EtOH 30%)
ACh in guinea pig ileum
IC
[80]

139 Gnaphaliin A
Gnaphalium liebmannii (Asteraceae)
Aerial parts (Hexane)
ACh, carbachol in guinea pig trachea
IC
[104]

140 Quercetin
Achillea millefolium (Asteraceae)
Whole plant infusion (MeOH 40%)
ACh, CaCl₂, H, PE, serotonin in rat ileum
IC
[97]

Psidium guajava (Myrtaceae)
Leaf extract (MeOH)
Peristalsis in guinea pig ileum
IC
[105]

Drosera madascariensis (Droseraceae)
Leaf extract (EtOH 70%)
Carbachol, H, PGF2 in guinea pig ileum and trachea
IC
[106]

Drosera rotundifolia (Droseraceae)
Aerial parts (EtOH 70%)
Carbachol in guine pig ileum
IC
[107]

Morinda morindoides (Rubiaceae)
Leaf extract (Aqueous)
Ac, KCl in guinea pig ileum
IC
[46]

141 3-O-Methylquercetin
Rhamnus nakaharai (Rhamnaceae)
Stem bark (not reported)
Carbachol, H, KCl in guinea pig trachea
IC
[108]

142 3,4′-Dimethylquercetin
Artemisia abrotanum (Asteraceae)
Aerial part (MeOH 67%)
Carbachol in guinea pig trachea
IC
[109]

143 3,7-Dimethylquercetin
Artemisia abrotanum (Asteraceae)
Aerial part (MeOH 67%)
Carbachol in guinea pig trachea
IC
[109]

144 Isoquercetin
Conyza filaginoides (Asteraceae)
Leaf infusion [CHCl₃:MeOH (1:1)]
Spontaneous contraction in rat ileum
IC
[47]

Hedera helix (Araliaceae)
Aerial parts (EtOH 30%)
ACh in guinea pig ileum
IC
[80]

Drosera rotundifolia (Droseraceae)
Aerial parts (EtOH 70%)
Carbachol in guinea pig ileum
IC
[107]

Drosera madascariensis (Droseraceae)
Leaf extract (EtOH 70%)
Carbachol, H, PGF2 in guinea pig ileum and trachea
IC
[106]

Psidium guajava (Myrtaceae)
Leaf extract (MeOH)
Peristalsis in guinea pig ileum
IC
[105]

145 Quercetin 3-α-rhamnoside or Quercitroside
Psidium guajava (Myrtaceae)
Leaf extract (MeOH)
Peristalsis in guinea pig ileum
IC
[105]

Morinda morindoides (Rubiaceae)
Leaf extract (Aqueous)
ACh, KCl in guinea pig ileum
IC
[46]

146 Quercetin 3-O-β-L-arabinoside
Psidium guajava (Myrtaceae)
Leaf extract (MeOH)
Peristalsis in guinea pig ileum
IC
[105]

147 Quercetin 3-O-β-D-galactoside
Psidium guajava (Myrtaceae)
Leaf extract (MeOH)
Peristalsis in guinea pig ileum
IC
[105]

Drosera madascariensis (Droseraceae)
Leaf extract (EtOH 70%)
Carbachol, H, PGF2 in guinea pig ileum and trachea
IC
[106]

148 Quercetin 3-O-β-gentiobioside 3-O-β-D-
Morinda morindoides (Rubiaceae)
Leaf extract (Aqueous)
ACh, KCl in guinea pig ileum
IC
[46]

Glucopyranosylquercetin
Drosera rotundifolia (Droseraceae)
Aerial parts (EtOH 70%)
Carbachol in guinea pig ileum
EO
[107]

149 Centaureidin
Artemisia abrotanum (Asteraceae)
Aerial part (MeOH 67%)
Carbachol in guinea pig trachea
IC
[109]

150 Casticin or Vitexicarpin
Artemisia abrotanum (Asteraceae)
Aerial part (MeOH 67%)
Carbachol in guinea pig trachea
IC
[109]

151 Prunetol or Sophoricol
Genista tridentata (Papilionaceae)
Not reported
AC, electric field stimulation, 6-oxo PGE1 in guinea pig ileum
IC
[110]

152 Boeravinone E
Boerhaavia diffusa (Nyctaginaceae)
Root infusion (MeOH)
ACh in guinea pig ileum
IC
[111]

153 4,6,11-trihydroxy-9-methoxy-10-methyl-6,12-dihydro-5,7-dioxatetraphen-12-one
Boerhaavia diffusa (Nyctaginaceae)
Root infusion (MeOH)
ACh in guinea pig ileum
IC
[111]

154 Boeravinone G
Boerhaavia diffusa (Nyctaginaceae)
Root infusion (MeOH)
ACh in guinea pig ileum
IC
[111]

155 (2R,3S,2”R,3”R)-Manniflavonone
Garcinia buchananii (Clusiaceae)
Stem bark (EtOH 70%)
Bay K 8644 in mouse ileum
IC
[112]

156 Hyperoside
Hypericum perforatum (Hypericaceae)
Aerial parts (EtOH 70%)
KCl in rabbit jejunum
IC
[82]

157 Chrysoeriol
Artemisia copa (Compositae)
Aerial parts (Aqueous)
KCl, PE, S in rat aorta
E
[98]

Aspalathus linearis (Fabaceae)
Commercial (Aqueous)
KCl in rabbit jejunum
IC
[102]

158 Spinacetin
Artemisia copa (Compositae)
Aerial parts (Aqueous)
KCl, PE, S in rat aorta
E
[98]

159 Vicenin 2
Perilla frutescens (Lamiaceae)
Commercial (Aqueous)
ACh, BaCl₂ i rat ileum
IC
[113]

160 Orientin
Aspalathus linearis (Fabaceae)
Commercial (Aqueous)
KCl in rabbit jejunum
IC
[102]

Phenylmetanoids

161 Salicylic acid methyl ether
Brickellia veronicifolia (Asteraceae)
Aerial parts [CH₂Cl₂:MeOH (1:1)]
Gastrointestinal motility test in mouse
E
[75]

162 O-Anisic acid or 6-Methoxysalicylic acid
Brickellia veronicifolia (Asteraceae)
Aerial parts [CH₂Cl₂:MeOH (1:1)]
Gastrointestinal motility test in mouse
E
[75]

163 Protocatechuic acid
Hedera helix (Araliaceae)
Aerial parts (EtOH 30%)
ACh in guinea pig ileum
IC
[80]

164 Benzyl 2,5-dimethoxybenzoate
Brickellia veronicifolia (Asteraceae)
Aerial parts [CH₂Cl₂-MeOH (1:1)]
Gastrointestinal motility test in mouse
E
[75]

Phenylethanoids

165 O-Methylbalsamide
Zanthoxylum hyemale (Rutaceae)
Stem bark infusion (EtOH)
ACh, BaCl₂ in rat ileum
IC
[114]

166 (-)-Tembamide
Zanthoxylum hyemale (Rutaceae)
Stem bark infusion (EtOH)
ACh, BaCl₂ in rat ileum
IC
[114]

167 O-Methyltembamide
Zanthoxylum hyemale (Rutaceae)
Steam bark infusion (EtOH)
ACh, BaCl₂ in rat ileum
IC
[114]

Phenylpropanoids

168 Eugenol
Ocimum gratissimum (Lamiaceae)
Not reported
ACh, KCl in guinea pig ileum
EO
[34]

169 Rosemaric acid or Rosemary acid or trans-Rosmarinic acid
Thymus vulgaris (Lamiaceae)
Commercial
KCl in rat trachea
IC
[100]

170 trans-Chlorogenic acid
Hedera helix (Araliaceae)
Aerial parts (EtOH 30%)
ACh in guinea pig ileum
IC
[80]

171 cis-Chlorogenic acid
Hedera helix (Araliaceae)
Aerial parts (EtOH 30%)
ACh in guinea pig ileum
IC
[80]

172 3,5-Dicaffeoylquininic acid
Hedera helix (Araliaceae)
Aerial parts (EtOH 30%)
ACh in guinea pig ileum
IC
[80]

173 Verbascoside
Plantago lanceolata (Plantaginaceae)
Aerial part infusion (EtOH 20%)
ACh, BaCl₂, H, KCl in guinea pig ileum and trachea
E
[99]

174 Isoacteoside or Isoverbascoside
Plantago lanceolata (Plantaginaceae)
Aerial part infusion (EtOH 20%)
ACh, BaCl₂, H, KCl in guinea pig ileum and trachea
E
[99]

175 Plantamajoside or Plantamoside or Purpureaside A
Plantago lanceolata (Plantaginaceae)
Aerial part infusion (EtOH 20%)
ACh, BaCl₂, H, KCl in guinea pig ileum and trachea
E
[99]

176 Lavandulifolioside
Plantago lanceolata (Plantaginaceae)
Aerial part infusion (EtOH 20%)
ACh, BaCl₂, H, KCl in guinea pig ileum and trachea
E
[99]

177 Echinacoside
Cistanche tubulosa (Orobanchaceae)
No reported (EtOH)
KCl, PE in rat aorta
IC
[115]

178 Schisandrin A or Wuweizisu A
Schisandra chinensis (Schisandraceae)
Academic
Spontaneous contractions in rat colon
IC
[116]

179 Schisandrin B or Wuweizisu B
Schisandra chinensis (Schisandraceae)
Fruit decoction (Aqueous)
ACh, KCl, S in guinea pig ileum
IC
[117]

180 Schisandrol B
Schisandra chinensis (Schisandraceae)
Fruit decoction (Aqueous)
ACh, KCl, S in guinea pig ileum
IC
[117]

Stilbenoids

181 Aloifol II or Dendrophenol or Moscatilin
Nidema boothii (Orchidaceae)
Whole plant infusion [CH₂Cl₂-MeOH 1:1)]
Spontaneous contraction in guinea pig ileum
IC
[118]

182 Batatasin III
Nidema boothii (Orchidaceae)
Whole plant infusion [CH₂Cl₂-MeOH 1:1)]
Spontaneous contraction in guinea pig ileum
IC
[118]

Scaphyglottis livida (Orchidaceae)
Whole plant infusion [CH₂Cl₂-MeOH (1:1)]
ACh, BaCl₂, H in rat ileum
IC
[119]

183 4-[2-(3-hydroxy-5-methoxyphenyl)ethyl]-2-methoxyphenol
Scaphyglottis livida (Orchidaceae)
Whole plant infusion [CH₂Cl₂-MeOH (1:1)]
ACh, BaCl₂, H in rat ileum
IC
[119]

184 Gigantol
Nidema boothii (Orchidaceae)
Whole plant infusion [CH₂Cl₂-MeOH (1:1)]
Spontaneous contraction in guinea pig ileum
IC
[118]

185 Coelonin
Scaphyglottis livida (Orchidaceae)
Whole plant infusion [CH₂Cl₂-MeOH (1:1)]
ACh, BaCl₂, H in rat ileum
IC
[119]

186 Erianthridin
Maxillaria densa (Orchidaceae)
Whole plant infusion [CHCl₃-MeOH (1:1)]
ACh, BaCl₂, H in rat ileum
IC
[120]

187 Ephemeranthoquinone
Nidema boothii (Orchidaceae)
Whole plant infusion [CH₂Cl₂-MeOH (1:1)]
Spontaneous contraction in guinea pig ileum
IC
[118]

188 Nudol
Maxillaria densa (Orchidaceae)
Whole plant infusion [CHCl₃-MeOH (1:1)]
ACh, BaCl₂, H in rat ileum
IC
[120]

189 3,4- dimethoxyphenanthrene-2,5-diol
Maxillaria densa (Orchidaceae)
Whole plant infusion [CHCl₃-MeOH (1:1)]
ACh, BaCl₂, H in rat ileum
IC
[120]

190 Denthyrsinin
Scaphyglottis livida (Orchidaceae)
Whole plant infusion [CH₂Cl₂-MeOH (1:1)]
ACh, BaCl₂, H in rat ileum
IC
[119]

191 Gymnopusin
Maxillaria densa (Orchidaceae)
Whole plant infusion [CHCl₃-MeOH (1:1)]
ACh, BaCl₂, H in rat ileum
IC
[120]

192 Fimbriol A
Maxillaria densa (Orchidaceae)
Whole plant infusion [CHCl₃-MeOH (1:1)]
ACh, BaCl₂, H in rat ileum
IC
[120]

Curcuminoid

193 (1E,5S,6E)-5-hydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadien-3-one
Curcuma longa (Zingiberaceae)
Macerated rhizome (EtOH 70%)
ACh, BaCl₂, CaCl₂, H, KCl, O in guinea pig Ileum and rat uterus
IC
[121]

Benzofurans and Related

194 (+)-Vitisin C
Vitis spp. (Vitaceae)
Stem infusion (MeOH)
PE in rabbit aorta
IC
[122]

195 Butylphthalide
Ligusticum wallichii (Umbelliferae)
Rhizome (hydrodistillation)
CaCl₂, KCl in rat aorta
EO
[123]

196 cis-Butylidenephthalide
Ligusticum wallichii (Umbelliferae)
Rhizome (hydrodistillation)
CaCl₂, KCl in rat aorta
EO
[123]

197 Ligustilide A or cis-Ligustilide
Ligusticum wallichii (Umbelliferae)
Rhizome (hydrodistillation)
CaCl₂, KCl in rat aorta
EO
[123]

198 12-acetoxytremetone
Helichrysum italicum ssp. italicum (Asteraceae)
Flowers (EtOH)
ACh, BaCl₂ in mouse ileum
IC
[124]

199 1-[(2R)-2-(3-hydroxyprop-1-en-2-yl)-2,3-dihydro-1-benzofuran-5-yl]ethan-1-one
Helichrysum italicum ssp. italicum (Asteraceae)
Flowers (EtOH)
ACh, BaCl₂ in mouse ileum
IC
[124]

Alkaloids

200 Indicaxanthin
Opuntia ficus indica (Cactaceae)
Fruit pulp infusion (Aqueous)
Carbachol, KCl in mouse ileum
IC
[125]

201 Papaverine
Daucus carota (Apiaceae)
Seed infusion (MeOH 90%)
ACh, BaCl₂, H, KCl, S, O in dog trachea, guinea pig, rabbit, rat ilea, rat uterus
IC
[126]

202 Higenamine
Nandina domestica (Berberidaceae)
Fruit (Aqueous)
ACh, H, KCl in guinea pig trachea
IC
[127]

203 Atherosperminine
Fissistigma glaucescens (Annonaceae)
Bark (MeOH)
Carbachol, KCl, LTC4, PGF2α, U46619 in guinea pig trachea
IC
[128]

204 (+)-Domestine or (+)-Nantenine
Platycapnos spicata (Fumariaceae)
Academic supplier
BaCl₂, CaCl₂, KCl, PE, S in rat aorta and atria
IC
[129]

205 10-Methylacridone
Citrus deliciosa (Rutaceae)
Root juice (MeOH)
Rabbit ileum
IC
[130]

206 Spermatheridine or liriodenin
Fissistigma glaucescens (Annonaceae)
Leaf infusion (MeOH)
Carbachol in canine trachea
IC
[131]

207 Citpressine I
Citrus deliciosa (Rutaceae)
Root juice (MeOH)
Rabbit ileum
IC
[130]

208 Jatrorhizine or Neprotine
Berberis aristata (Berberidaceae)
Institutional supplier
ACh, S, spontaneous contractions in rat ileum
IC
[132]

Coptis chinensis (Ranunculaceae)
Rhizoma (EtOH 70%)
ACh in guinea pig ileum
IC
[133]

209 Coptisine
Coptis chinensis (Ranunculaceae)
Rhizoma (EtOH 70%)
ACh in guinea pig ileum
IC
[133]

210 Escholine or Thalictrine
Mahonia aquifolium (Berberidaceas)
Cortex and fruit infusion
KCl, PE in rat aorta
IC
[134]

211 (+)-Isothebaine
Mahonia aquifolium (Berberidaceas)
Cortex and fruit infusion
KCl, PE in rat aorta
IC
[134]

212 (+)-Corytuberine
Mahonia aquifolium (Berberidaceas)
Cortex and fruit infusion
KCl, PE in rat aorta
IC
[134]

213 (+)-Isocorydine or Luteanine
Mahonia aquifolium (Berberidaceas)
Cortex and fruit infusion
KCl, PE in rat aorta
IC
[134]

214 (+)-Chelidonine or Stylophorine
Chelidonium majus (Papaveraceae)
Commercial supplier
BaCl₂, carbachol in guinea pig ileum
IC
[135]

215 (-)-8 beta-(4′-hydroxybenzyl)-2,3-dimethoxyberbin-10-ol
Aristolochia constricta (Aristolochiaceae)
Aerial part infusion (MeOH)
ACh, electrical contraction, H in guinea pig ileum
IC
[136]

216 3-O-methylconstrictosine
Aristolochia constricta (Aristolochiaceae)
Aerial part infusion (MeOH)
ACh, electrical contraction, H in guinea pig ileum
IC
[136]

217 3,5-di-O-methylconstrictosine
Aristolochia constricta (Aristolochiaceae)
Aerial part infusion (MeOH)
ACh, electrical contraction, H in guinea pig ileum
IC
[136]

218 5,6-dihydro-3,5-di-O-methylconstrictosine
Aristolochia constricta (Aristolochiaceae)
Aerial part infusion (MeOH)
ACh, electrical contraction, H in guinea pig ileum
IC
[136]

219 5,6-dihydroconstrictosine
Aristolochia constricta (Aristolochiaceae)
Aerial part infusion (MeOH)
ACh, electrical contraction, H in guinea pig ileum
IC
[136]

220 Constrictosine
Aristolochia constricta (Aristolochiaceae)
Aerial part infusion (MeOH)
ACh, electrical contraction, H in guinea pig ileum
IC
[136]

221 Isojuripidine
Solanum asterophorum (Solanaceae)
Leaf infusion (MeOH)
ACh, CaCl₂, H in guinea pig ileum
IC
[137]

222 Sarcodine
Sarcocca saligna (Buxaceae)
Whole plant (MeOH)
ACh, KCl in guinea pig ileum, rat stomach fundus, rabbit jejunum
IC
[138]

223 Saracorine or Sarcorine
Sarcococca saligna (Buxaceae)
Whole plant infusion (MeOH)
ACh, KCl in rabbit jejunum
IC
[139]

224 Saracocine
Sarcocca saligna (Buxaceae)
Whole plant (MeOH)
ACh, KCl in guinea pig ileum, rat stomach fundus, rabbit jejunum
IC
[138]

225 Alkaloid C
Sarcocca saligna (Buxaceae)
Whole plant (MeOH)
ACh, KCl in guinea pig ileum, rat stomach fundus, rabbit jejunum
IC
[138]

226 (-)-Pachyaximine A
Sarcococca saligna (Buxaceae)
Whole plant infusion (MeOH)
ACh, KCl in rabbit jejunum, KCl
IC
[139]

227 (-)-(R)-Geibalansine or (-)-R-Geilbalansine
Zanthoxylum hyemale (Rutaceae)
Stem bark infusion (EtOH)
ACh, BaCl₂ in rat ileum
IC
[114]

228 Hyemaline
Zanthoxylum hyemale (Rutaceae)
Stem bark infusion (EtOH)
ACh, BaCl₂ in rat ileum
IC
[114]

229 Theophylline
Fissistigma glaucescens (Annonaceae)
Leaf infusion (MeOH)
Carbachol in canine trachea
IC
[131]

230 Carboxyscotangamine A
Scopolia tangutica (Solanaceae)
Root (95% EtOH)
Carbachol in Chinese hamster ovarian cell
IC
[140]

231 Scotanamine A
Scopolia tangutica (Solanaceae)
Root (95% EtOH)
Carbachol in Chinese hamster ovarian cell
IC
[140]

232 Piperine
Piper nigrum (Piperaceae)
Fruit (EtOH)
Ileum loop in mice
IC
[141]

Amines

233 Scotanamine B
Scopolia tangutica (Solanaceae)
Root (95% EtOH)
Carbachol in Chinese hamster ovarian cell
IC
[123]

234 Scotanamine C
Scopolia tangutica (Solanaceae)
Root (95% EtOH)
Carbachol in Chinese hamster ovarian cell
IC
[140]

235 Scotanamine D
Scopolia tangutica (Solanaceae)
Root (95% EtOH)
Carbachol in Chinese hamster ovarian cell
IC
[140]

236 N¹-Caffeoyl-N³-dihydrocaffeoylspermidine
Scopolia tangutica (Solanaceae)
Root (95% EtOH)
Carbachol in Chinese hamster ovarian cell
IC
[140]

237 N¹, N¹⁰-Bis(dihydrocaffeoyl)spermidine
Scopolia tangutica (Solanaceae)
Root (95% EtOH)
Carbachol in Chinese hamster ovarian cell
IC
[140]

238 Caffeoylputrescine
Scopolia tangutica (Solanaceae)
Root (95% EtOH)
Carbachol in Chinese hamster ovarian cell
IC
[140]

Isothiocyanates

239 Redskin or Senfoel
Cruciferous vegetables (Brassicaceae)
Commercial source
ACh, electrical contraction in mouse ileum
IC
[142]

Alcohols

240 (3E)-4-(3,4-dimethoxyphenyl)but-3-en-1-ol
Zingiber cassumunar (Zingiberaceae)
Chemically synthesized
O in rat uterus
IC
[143]

Ketones

241 2-Decanone
Ruta chalepensis (Rutaceae)
Leaf (EtOH 70%)
KCl in rat ileum
E
[144]

242 2-Undecanone
Ruta chalepensis (Rutaceae)
Leaf (EtOH 70%)
KCl in rat ileum
E
[144]

243 2-Tridecanone
Ruta chalepensis (Rutaceae)
Leaf (EtOH 70%)
KCl in rat ileum
E
[144]

244 Latifolone
Ferula heuffelii (Apiaceae)
Underground part (CHCl₃)
ACh, KCl in rat ileum
IC
[85]

245 Dshamirone
Ferula heuffelii (Apiaceae)
Underground part (CHCl₃)
ACh, KCl in rat ileum
IC
[85]

Phenolic compounds

246 6-(4-hydroxy-3-methoxyphenyl)-hexanonic acid (HMPHA)
Pycnocycla spinosa (Umbelliferae)
Aerial parts (MeOH)
KCl in rat ileum
IC
[145]

247 Isovanillin
Pycnocycla spinosa (Umbelliferae)
Aerial parts (MeOH)
KCl in rat ileum
IC
[146]

248 Iso-acetovanillon
Pycnocycla spinosa (Umbelliferae)
Aerial parts (MeOH)
KCl in rat ileum
IC
[146]

IC = isolated compound, E = extract, EO = essential oil, ACh = acetylcholine, O = oxytocin, PMA = β-Phenylethyl amsine, PGF = Prostaglandin F2α, H = histamine, S = serotonin.

Some advantages of performing ex vivo experiments are as follows: (i) different substances can be evaluated in fresh tissues without absorption factors, metabolic excretion or interference due to nerve reflexes; (ii) it is possible to quantify the effect produced by a precisely determined drug; and (iii) it is easier to obtain dose-effect curves, such as the smooth muscle where the contraction obtained under the influence of a spasm or in tissue homogenates is measured by determination of the enzyme activities [172, 174].

5.2. Guinea Pig Ileum and Rat Stomach

The ileum is removed and cut in strips of approximately 2 cm long and then placed in a bath filled with an isotonic solution as mentioned earlier. Electrophysiological studies are performed by graphically recording the contractions with the aid of a transducer, which is calibrated 30 min before the treatment begins. A range of 0.01 to 0.03 μM is generally used to determine dose response curves of the antispasmodic substance [175].

In rats, the stomach is removed and the corpus and fundus are cut in strips of approximately 5 mm x 15 mm and placed on a prewarmed warm solution as mentioned before.

5.3. Compounds Used to Elicit a Spasmodic Activity

The main compounds used are acetylcholine, atropine, BaCl₂, carbachol, histamine, KCl, and serotonin.

Acetylcholine is a postganglionic neurotransmitter in the parasympathetic neurons that innervate the intestine. The response to acetylcholine is regulated by activation of the two types of muscarinic receptors: M2 and M3 [176]. The activation of these receptors causes contractions by increasing the intracellular concentration of Ca²⁺ via IP3 [176]. Atropine is a competitive reversible antagonist of muscarinic acetylcholine receptors M1, M2, M3, M4, and M5.

Different substances are used to produce contractions. For example, BaCl₂ induces contractions by mobilizing membrane-bound Ca²⁺ [177], carbachol is a cholinomimetic drug (cholinergic agonist) that binds and activates acetylcholine receptors [178], histamine acts by either accelerating the release of acetylcholine or interacting supra-additively with the acetylcholine at the smooth muscle [179], whereas KCl increases the voltage-operated Ca²⁺ channel activity by increasing intracellular free Ca²⁺ in smooth muscle [180]. Serotonin is also an important neurotransmitter mainly stored in the digestive tract, affecting the secretory and motor activities. At high concentrations, it acts as a vasoconstrictor by contracting endothelial smooth muscle directly or by potentiating the effects of other vasoconstrictors [181, 182].

6. Antispasmodic Activity of Natural Compounds

Compounds isolated from terrestrial plants have shown the ability to function as antispasmodic compounds. The chemical group with the highest number of members of antispasmodic compounds is the monoterpenoid group (41 compounds) followed by flavonoids (35 compounds), alkaloids (with 33 compounds), and triterpenes with 31 (Figure 1). Although we summarize in Table 3 248 compounds, in most of the cases the mechanism behind their activity has not been elucidated.

Figure 1: Number of isolated compounds with antispasmodic activity. The total number was obtained from Table 3. “Others” is the sum of the compounds belonging to alcohols, amines, benzofurans, chalcones, coumarins, curcuminoids, isothiocyanates, ketones, phenolic, phenylmethanoids, phenylethanoids, glucinols, and phloroglucinols.

7. Mutagenicity

Studies related to the mutagenicity of antispasmodics are very scarce. This topic has been underestimated when testing the bioactivities of ethnomedicinal plants. Probably the most useful method to determine the mutagenicity of natural products or plant extracts is the Ames method [183]. This test is based on the rate of mutations detected in genetically modified strains of Salmonella typhimurium. Moreover, this test has also been developed to detect mutagenicity of metabolized compounds in the liver. In this situation, a mixture of liver enzymes (S9 microsomal fraction) is used to mimic the metabolites that will be produced in the liver [184].

Few studies have been performed to determine the mutagenicity of natural products with antispasmodic activity. For example, the flavonoids quercetin and luteolin were tested using the Ames method and the appearance of point mutations in four of the tested bacterial strains was shown [185]. In another study, the extracts of the plants Brickellia veronicaefolia, Gnaphalium sp., Poliomintha longiflora, and Valeriana procera were studied. Compounds isolated from these plants are listed as antispasmodic compounds (Table 3). Results of the mutagenicity test indicated that Gnaphalium sp., Poliomintha longiflora (used in the Mexican cuisine and as a traditional medicine), and Valeriana procera induced mutagenesis in the tested bacterial strain [186].

8. Chemical Similarities between Natural and Synthetic Antispasmodic Compounds

To determine whether or not there is an analogy between synthetic (Table 4) and natural antispasmodic compounds, the structures of both groups were compared. Results showed that no similarities were found except for alkaloids, amines, and amino acids.

Table 4: Synthetic antispasmodic compounds used in medicine.

Synthetic compound
Receptor targeted
Main use

Alkaloids

Chlorzoxazone
Prevents release of histamine
Muscular spasm

Pancuronium
Nicotinic acetylcholine
Muscle relaxant

Riluzole
Sodium channels
Amyotrophic lateral sclerosis

Rocuronium
Antagonist of neuromuscular junction
Muscle relaxant and anaesthesia

Tizanidine
α₂ adrenergic agonist
Muscle relaxant

Vecuronium
Nicotinic acetylcholine
Muscle relaxant and anaesthesia

Curcuminoids

Atracurium
Nicotinic acetylcholine
Muscle relaxant and anaesthesia

Cisatracurium
Nicotinic acetylcholine
Muscle relaxant and anaesthesia

Mivacurium
Nicotinic acetylcholine
Muscle relaxant and anaesthesia

Methylpropanoid

Diazepam

Anxiety, alcohol withdrawal syndrome, muscle spasms, seizures, and restless legs syndrome

Prograbide

Epilepsy

Orphenadrine

Skeletal muscle relaxant that is used for the treatment of acute muscle aches, pain, or spasms.

Phenylpropanoids

Baclofen

Spinal cord injury, cerebral palsy, and multiple sclerosis

Idrocilamide
Prevents release of intracellular Ca²⁺
Skeletal muscle relaxant and muscular pain

One of the main differences is that commercial alkaloids are methylated in their nitrogen to make them positive, increasing their solubilities because of salt formation. In contrast, natural products have no positive nitrogen, rendering the molecule neutral and pH dependent. Thus, the compound may or may not be protonated, resulting in a change in its solubility and consequently a change on the targeting tissues.

The comparison can perhaps be focused on the distribution of charges rather than by functional groups or families of compounds, emphasizing the electron distribution. For example, a physical characterization such as the heat of formation, the surface electrostatic potential, the molecular weight, the surface tension, the refractive index, the lipophilicity, and others has been used to characterize the structure-activity relationship of alkaloids extracted from the Amaryllidaceae family [187]. These alkaloids were selected because of their ability to inhibit the effect of the acetylcholinesterase enzyme.

Of special interest is the natural compound salvinorin A isolated from the Mexican hallucinogenic Salvia divinorum (Lamiaceae) used in the traditional medicine as an antidiarrheal. It has been reported that this compound inhibited the intestinal motility through the activation of other receptors such as κ-opioid receptors (KORs). Upon inflammation of the gut, the cannabinoid C, B₁, and KOR receptors are upregulated. It appears that salvinorin A interacts in the cross-talk between these receptors with a reduction of the inflammation as demonstrated in murine and guinea pig models [188, 189].

Analysis of the similarities between synthetic and natural antispasmodic structures is depicted in Table 5.

Table 5: Similarities between natural and synthetic compounds.

Synthetic
Natural

9. Conclusions

A large number of natural products with antispasmodic activities have been reported. Although the use of plants in traditional medicine is still relevant, it is necessary to perform new studies to elucidate the mechanism of action of antispasmodics. Moreover, more information about cytotoxicity and mutagenesis should be explored to ensure that these compounds are safe for consumption. The findings of this study corroborated the need for safety studies on plants extensively used for primary health care in countries such as Mexico. Such studies must be carried out before continuing with the widespread use of some species, which may provoke long-term and irreversible damage.

Conflicts of Interest

The authors declare no conflicts of interest.

Acknowledgments

The authors thank Marilyn Robertson for helpful discussion.

Supplementary Materials

This file contains the structures of the compounds described in the main text. (Supplementary Materials)

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