Pharmacology of Poppy Alkaloids: Minor Opium Alkaloids

2015

The pharmacology and biology of minor opium alkaloids have been surveyed previously in two comprehensive reviews ().

Thebaine

The pharmacology of thebaine was summarized by Reynolds and Randall in 1957 and studied comprehensively by a WHO Advisory Group in 1980.

The pharmacological actions of thebaine in various isolated organs have been studied. Thebaine can induce a temporary decrease in blood pressure in anaesthetized dogs and this depressor effect showed a marked tachyphylaxis. In isolated guinea pig atrium, thebaine decreased the heart rate and contractions depending on the concentration. In isolated rabbit ileum it decreased the peristaltic movement and contractions (). The predominant effect of thebaine is stimulation of the central nervous system. In the mouse, rabbit, cat and dog increases in motor activity and reflex excitability were observed at doses around 2-10mg/kg s.c. or i.m. The Straub-tail response was noted only occasionally. The effects of thebaine on body temperature and respiration have also been studied. Convulsions were observed in almost all species of animals including the frog, pigeon, mouse, guinea pig, cat and dog. Transient tremors, restlessness and convulsions were observed in the rhesus monkey. The convulsant action of thebaine was studied by electrophysiological analysis (). Naloxone antagonized the convulsions induced by thebaine in mice, but it was ten times less effective versus thebaine than it was versus heroin (). Thebaine was noted to produce a moderate decrease of catecholamine levels in heart and brain ().

Detailed analgesic studies were performed in mice (). Compared to morphine, thebaine is a more effective narcotic but a weaker analgesic. Thebaine is inactive in the tail flick and writhing tests, but it is active in the hot plate and Nielsen tests. However, doses in the higher range of the dose — response curves produced convulsions. In isolated organ preparations (GPI and MVD) thebaine possesses 0.3 times the potency of morphine. The actions of thebaine are partially reversed by naloxone, but these effects are presumed not specific opioid-like effects ().

Repeated administration of thebaine for six weeks in rhesus monkeys did not result in the development of tolerance to convulsant effects.

In rats the physical dependence potential of thebaine was very low. Thebaine did not precipitate morphine withdrawal signs in chronic spinal dogs (). Nevertheless naloxone produced very mild withdrawal signs in spinal dogs treated chronically with thebaine. Thebaine did not substitute for morphine in morphinedependent rhesus monkeys. On the other hand, definite withdrawal signs were observed upon abrupt withdrawal of thebaine in the monkeys treated with i.v. thebaine for 31 days ().

The toxicity of thebaine was examined in rabbits. These studies indicated that thebaine exhibits marked convulsive effects (). Thebaine is far more toxic than morphine ().

The metabolism of tritium-labelled thebaine was studied in rats and several metabolites were detected. Codeine, norcodeine, normorphine, morphine and 14-hydroxycodeinone were identified as minor metabolites. Oripavine was the major metabolite (). Metabolism was also examined in rhesus monkeys (). Five substances were detected and separated by means of thin layer chromatography in the urine. Oripavine and N-nororipavine have been identified by gas chromatography — mass spectrometry (GC — MS) analysis. It was reported that oripavine was the major metabolite of thebaine in vitro (). Thebaine was incubated with rat liver microsomes in these experiments. The transformation of thebaine to oripavine, codeine, and morphine has been reported in rat liver and kidney (). Opioid receptor binding of thebaine was studied in rat brain membranes, but it had very weak affinity (). Thebaine displays some cytotoxic effects in vitro ().

Oripavine

The pharmacology of oripavine was the subject of a comprehensive study by a WHO Advisory Group (1981).

Single doses of oripavine administered intravenously manifested a decrease in spontaneous motor activity in rats and in rhesus monkeys. Additionally, tremors and vomiting were also observed in monkeys.

Its analgesic potency in mice is much higher than that of thebaine and is comparable to that of morphine in both tail flick and writhing tests in which thebaine is reported to be inactive. The analgesic activity of oripavine was also studied in the mouse and rat with the hot plate method after subcutaneous drug administration. Peak analgesic effects in the mouse and rat were observed 20 minutes after drug administration and the effects lasted for about 40-60 minutes. Oripavine appears to have analgesic potency of the same order of magnitude as morphine in these species, but has a low therapeutic index because of its high toxicity. Signs of oripavine toxicity in both species were clonic-tonic convulsions followed by death. The toxicity of oripavine and morphine in the mouse did not appear to be antagonized by pre-treatment with naloxone. Toxicity does not appear to be mediated at the opioid receptor, however oripavine did show some cross tolerance with morphine, but did not appear to suppress morphine abstinence in the mouse and rat ().

Oripavine possesses a weak morphine-antagonistic property, as evidenced by its partial precipitation of morphine withdrawal signs in morphine-dependent nonwithdrawn monkeys.

The administration of oripavine resulted in the development of physical dependence in rats. Obvious morphine-like withdrawal signs were precipitated by naloxone. Oripavine did not suppress the withdrawal signs of morphine-dependent rhesus monkeys. However, it is known that the physical dependence potential of morphine antagonists or partial agonists may not be demonstrable because the antagonistic property of these drugs may prevent the suppression of morphine withdrawal signs.

The metabolism of oripavine has not yet been reported.

Neopine

The actions of neopine closely resemble those of codeine. Clinical trials, however, have shown this drug to be less effective than codeine when employed in doses of 15-30mg. In frogs, slight drowsiness followed by increased reflexes is seen with small doses, and larger doses produce tetanus. In rabbits some narcotic effect is seen, but with doses of 80mg or more, convulsions and death occur. No changes were observed in the size of the pupil. In the dog the bronchioles become constricted ().

Salutaridine

Salutaridine does not display significant effects on human platelet aggregation (). Racemic Salutaridine can be considered as a partial agonist of the GABA (γ-aminobutyric acid)-benzodiazepine receptor complex ().

Pseudomorphine

Pseudomorphine is very insoluble in saline fluids and exerts little or no action when administered by the oral or subcutaneous route. However, when given intravenously even in quite small doses, very definite effects are produced, particularly on the circulation. The drug exhibits practically none of the direct actions of morphine on the central nervous system. Some general depression and uncoordination have been described, but neither true narcosis nor primary respiratory failure have been observed ().

Conflicting results have been reported with regard to the occurrence of convulsions after the administration of pseudomorphine; at any rate, the convulsant action seems to be much weaker than that of morphine. Emesis is a common symptom and defecation usually follows soon after injection. As already stated, the most pronounced effects following intravenous injection are exerted on the circulatory system, and indeed some investigators attribute most of the acute effects of pseudomorphine to acute circulatory depression resulting chiefly from peripheral vasodilatation. The vascular effects of this compound appear to be qualitatively similar to those of morphine, but are much more intense. In the dog and cat, the abrupt fall in blood pressure seems to be the result of marked dilatation of muscular and cutaneous blood vessels; the depressor effect does not depend on the integrity of the medulla. The isolated heart is somewhat depressed although coronary flow seems to be slightly increased. Hypotension is not observed in rabbits, rats, or guinea pigs.

Pseudomorphine readily produces acute tolerance to the circulatory effect, not only to itself, but to morphine, codeine, and heroin as well; this acute tolerance is limited to the circulatory effects. The intravenous injection of pseudomorphine results in symptoms which superficially resemble those observed during withdrawal of morphine from chronically treated tolerant dogs (). Pseudomorphine is one of the metabolites of morphine () and it is converted into a less toxic substance in the mouse ().

Laudanosine

Laudanosine has a convulsant action in anaesthetized curarized dog and this effect was suppressed by pentobarbital (). Anaesthetic drugs administered before the convulsive stimulus increased the dose of laudanosine necessary to produce seizures (). The pharmacology of laudanosine has been studied extensively because laudanosine is a principal metabolite of atracurium (). EEG effects of laudanosine were examined in an animal model of epilepsy. It was found that no increase of seizure activity was produced by mean laudanosine concentrations and the routine use of atracurium is unlikely to provoke seizures, even in the presence of an epileptogenic focus ().

Laudanosine enhanced the release of 3H-noradrenaline in isolated right atria of guinea pigs (). This effect of laudanosine may explain some of the unwanted effects seen following administration of atracurium.

Laudanosine crosses readily the blood — brain barrier and can produce hypotension. It is excreted unchanged by the kidneys and its metabolites are excreted by both the kidneys and liver (). Metabolism of racemic laudanosine was studied in the dog, rabbit and man. Codamine and laudanine were detected among the metabolites ().

Aldehyde reductase or alcohol dehydrogenase enzymes have been found to be inhibited by laudanosine, protopine and berberine ().

Laudanine

In frogs, the effect of laudanine is similar to that of strychnine. Laudanine is noted to induce convulsions and larger doses cause paralysis. Similar effects were observed in pigeons. Small doses produced acceleration of respiration in rabbits, dogs and cats but higher doses induced tetany. Laudanine in small doses was also reported to cause a sudden rise in blood pressure ().

Reticuline

S-(+)-reticuline showed negative ionotrop effects in the papillary muscles of guinea pig heart (). Anti-inflammatory effects were also detected by the pouch granuloma method in mice ().

(-)-reticuline produces catalepsy and a decrease in locomotor activity in mice. It blocks locomotor activation and rotational behaviour induced by apomorphine, but not those induced by methamphetamine ().

Reticuline was reported to inhibit specific 3H-dopamine binding to dopamine receptors in tissue homogenates from rat corpora striata. The blockade of apomorphineinduced climbing behaviour was observed by reticuline in mice. Reticuline also blocked amphetamine-induced circling behaviour in mice, but it did not produce catalepsy at doses which blocked circling behaviour (). The administration of reticuline exerted a uterine inhibitory effect mainly related to a decrease in the concentration of cytosolic Ca2+ available for contraction (). Reticuline shows a low affinity to catecholamine receptors (). It has an inhibitory effect on indirectly stimulated contractions in frog sciatic nerve — sartorius muscle preparation, but produces almost no effect on directly stimulated contractions ().

Reticuline shows no anti-microbial activity ().

Protopine

Protopine — HCl (given intravenously in rats or rabbits) decreased the atrioventricular and intracardiac conductivity leading to a decrease in the frequency of cardiac contractions. A decrease in contractions induced by BaCl2 was also observed in the isolated intestinal segment of rat. Protopine displays anti-arrhythmic activity and is more effective than quinidine or novocainamide for CaCl2-induced and aconitine-induced cardiac arrhythmia in rats (). It has been suggested that the mechanism of the anti-arrhythmic effect of protopine is due to the suppression of the foci of heterotropic stimulation, a decrease in the excitability of myocardial cells and normalization of the catecholamine content in the myocardium.

In addition to its anti-arrhythmic effect, protopine also shows short-term hypotensive, ganglion-blocking, and spasmolytic properties (). Protopine is slightly weaker as a smooth muscle relaxant than papaverine. The smooth muscle relaxant mechanism of protopine may be due to inhibition of intracellular Ca2+ release (). In small doses it was reported to retard heart activity, decrease blood pressure and produce a sedative effect. However, large doses caused excitation and convulsions in the animals studied. Protopine showed inhibitory action in the isolated heart and muscle of frog, but it had a stimulating effect in the intestine of guinea pigs.

Protopine displays some inhibitory effect on tumours associated with considerable cytotoxic side effects (). The effects of protopine on the aggregation of platelets have been reported (). The mechanism of the action of protopine on rabbit platelet aggregation has been investigated in detail ().

It was also observed that protopine is an antagonist versus acetylcholine on mouse small intestine and an anti-spasmodic effect on the uterus was detected (). Protopine exhibits a significant decrease in intestinal muscle contractions and considerable cardioinhibitory, anti-arrhythmic, hypotensive and anti-pyretic effects were also found (). Antagonism of the lethal effect of histamine was observed in the guinea pig ().

α-Allocryptopine

The anti-arrhythmic action of α-allocryptopine was compared with quinidine. It was more effective than quinidine in preventing and treating aconitine-induced arrhythmia in rats (). α-allocryptopine prevented CaCl2-induced cardiac fibrillations in -20% of the rats studied (). The alkaloid has a local anaesthetic effect. The inhibitory effects of allocryptopine on the growth of tumours has been reported (). Allocryptopine produced no detrimental effects on peripheral blood or histology of organs and tissues after long-term administration in mice (). It was reported that allocryptopine, cryptopine and protopine enhance 3H-y-aminobutyric acid binding to rat brain synaptic membrane receptors, suggesting that these alkaloids have diazepam-like activity (). Allocryptopine has also been reported to have some anti-bacterial activity ().

Cryptopine

In mice cryptopine produced depression and asphytic twitches. Arterial blood pressure was lowered in cats and dogs and atropine could not prevent this effect. Nerve impulse conduction through cardiac vagal ganglia was blocked by cryptopine and the conduction through cervical sympathetic ganglia was not affected. Other effects of this compound were a transient stop of the heartbeat in frogs and an increase in the tone of uterine smooth muscle in pregnant rats ().

The anti-arrhythmic activity of cryptopine was compared with that of allocryptopine and the latter substance proved to be more effective in preventing the development of cardiac arrhythmia against aconitine (). Cryptopine shows some anti-bacterial effect ().

Magnofluorine

This alkaloid produced a decrease of motility and a slight relaxation of voluntary musculature in rabbits and mice. At toxic doses the cause of death was the cessation of respiratory movements ().

Magnofluorine and diacetylmagnofluorine have less curare-like activity than remerine hydroxymethylate () and they possess low hypotensive action (). Hypotensive effects are attributed to ganglion-blocking action (). Acetylation of magnofluorine resulted in an increase of toxicity. lonotrop activity of magnofluorine was demonstrated on isolated and perfused rat heart by Cave et al. (). Magnofluorine was reported to decrease arterial blood pressure in rabbits and induce hypothermia in mice. It induced contractions in isolated pregnant rat uterus and stimulated isolated guinea pig ileum ().

Magnofluorine displays cytotoxic () and anti-inflammatory activity (). Magnofluorine and corytuberine show no anti-microbial activity in vitro ().

The inhibition of protein formation has also been observed ().

Isoboldine

Isoboldine shows weak anti-microbial activity (). It has high affinity for the α1-adrenoreceptor in the binding assay (). Isoboldine inhibits adenyl cyclase () and aldol reductase ().

Corytuberine

Corytuberine causes increased reflex irritability in the frog and tonic convulsions with slightly increased irritability in guinea pigs and cats. Death from lethal doses results from asphyxia during convulsive seizures. This alkaloid accelerates respiration, stimulates the secretion of tears and saliva, and slows the pulse by stimulation of the vagus.

Corytuberine does not act as a mitotic poison in vitro. The methiodide of corytuberine displayed curare-like activity and a hypotensive effect ().

The neuroleptic, anti-convulsant and analgesic actions of corytuberine have been studied in mice — the substance elicited catalepsy and hypothermia and was anticonvulsant against harman and picrotoxin. It did not reduce nociception in hot plate and writhing tests. However, in low doses corytuberine antagonized the anti-nociceptive effect of morphine in the hot plate test ().

Narcotoline

The anti-tussive properties of narcotine, narcotoline, O-ethylnarcotoline, and O-benzylnarcotoline were examined in cats and guinea pigs. All compounds displayed anti-tussive potency with narcotine and O-ethylnarcotoline being the most active (). 3,4,5-trimethoxybenzoyl-narcotoline proved to be a cough reliever with mild depressive activity. It had no effect upon the respiratory centre ().

Narceine

Intravenous administration of narceine to rabbits stimulates the respiratory centre, and accelerates the frequency and increases the volume of respiration.

Narceine has an anti-tussive effect similar to that of codeine in animal models (mice, dogs, cats and rabbits) but without its analgesic potency; its anti-tussive effect is less potent than that of narcotine (). However, it has also been reported that narceine has no influence on the cough reflex of cats ().

A considerable depressant action on blood pressure was observed and a stimulating effect on intestinal peristalsis was detected (). Narceine has no analgesic action () and no convulsant action in the anaesthetized curarized dog ().

The toxicity of narceine was found to be similar in mice, rabbits and cats ().

Sanguinarine

The possible relationship of sanguinarine to glaucoma in epidemic tropical hydropsy which is frequent in India, has been the subject of numerous papers. Oil from Argemona mexicana L., whose seeds contain sanguinarine, is sometimes mixed with mustard oil which is commonly used in foodstuffs in India. It was found that the oil from A. mexicana causes glaucoma in epidemic hydropsy and this observation was corroborated by studies on rabbits and monkeys. Sanguinarine produced a decrease in intraocular pressure when injected i.v. into rabbits (). The large distribution of sanguinarine in Fapaveraceae plants was discussed and the relationship between the consumption of poppy seeds and the possible development of glaucoma was evaluated (). It was also reported that the frequent incidence of glaucoma in epidemic tropical hydropsy is the result of the effect of mustard oil contaminated or adulterated with the oil of seeds from A. mexicana containing sanguinarine ().

Sanguinarine has sympathicolytic, adrenolytic and local anaesthetic effects. It increases blood pressure, tonicity and intestinal peristalsis (). Sanguinarine possesses a large spectrum of anti-microbial activity in vitro () and displays low toxicity in rats when applied orally or intravenously (). The intercalating properties of sanguinarine with DNA have been examined in detail (). Sanguinarine shows some anti-tumour activity ().

The fraction of quaternary benzophenanthridine alkaloids from roots of Chelidonium magus containing sanguinarine has been tested for anti-inflammatory activity in rats. On the basis of its low toxicity, high anti-inflammatory activity and anti-microbial action it is recommended for medical use in the treatment of oral anti-inflammatory processes (). Sanguinarine exhibits anti-plaque activity in humans. For its plaqueretentive properties in combination with antimicrobial and anti-inflammatory effects, sanguinarine has been a component of toothpastes and oral rinses sold in the United States since 1984 ().

Sanguinarine inhibits liver enzymes and acetylcholine esterase ().

Dihydrosanguinarine

Dihydrosanguinarine and sanguinarine were reported to inhibit cyclic AMP phosphodiesterase (), and the inhibition of reverse transcriptase activity was also observed by these alkaloids (). Dihydrosanguinarine displays a lower toxicity than sanguinarine in rats ().

Scoulerine

Scoulerine shows sedative activity in mice (), and it is inactive as an anti-tussive. Scoulerine has been noted to prevent apomorphine-induced emesis in dogs () and to decrease locomotor activity in mice. This effect is mediated primarily by the cerebral cortex and secondarily by direct effect on the muscles (). It has an affinity for the dopamine receptors in brain ().

Canadine

Weak anti-bacterial effects of canadine () have been reported. Canadine inhibits the liver alcohol dehydrogenase enzyme (). It has some sedative effect in mice ().

Stepholidine

The pharmacology of Stepholidine has been investigated in detail because this alkaloid has been detected in numerous medicinal plants in Japan and China.

Stepholidine binds to dopamine receptors in rat brain. It is an antagonist of D1 dopamine receptors, but it behaves as an agonist in a supersensitive state of the receptor (). Stepholidine displays analgesic and anti-pyretic actions in mice and rabbits and it is interesting that tolerance to the analgesic effect of this substance did not develop. Prolonged administration of Stepholidine did not induce dependence ().

The interaction of stepholidine with opioid analgesics has been studied. Stepholidine potentiated the analgesic effects of dihydroetorphine or pethidine (). Stepholidine lowered blood pressure in anaesthetized dogs and rats. This hypotensive effect is mainly due to stimulation of the presynaptic α2-adrenoreceptors (), but the regulation of central dopamine receptors may take part in the hypotensive action ().

Stepholidine does not show anti-microbial activity ().

Isocorypalmine

Isocorypalmine showed inhibitory action on blood platelet aggregation induced by collagen, arachidonic acid, and ADP in vitro ().

Berberine

Berberine has some therapeutic value and is being used in the treatment of gastrointestinal disorders. The toxicity of berberine sulphate was studied in rats and was shown to display low toxicity by oral administration (). Berberine sulphate produced a reversible hypotension in the anaesthetized rat, and it increased the mortality in guinea pigs and dogs receiving safe doses of histamine. Berberine potentiated apomorphineinduced emesis in dogs. It decreased the urine volume and urinary concentrations of Na+, Ch ions in conscious saline-loaded rats. Berberine lowered the rectal temperature in normal rats and was three times more effective than sodium salicylate in decreasing fever induced by Brewer’s yeast. This finding confirms its traditional use as an antipyretic (). Berberine chloride displays anthelmintic activity in mice against Syphacia obvelata (). The pharmacokinetics of berberine were studied in rats, and after i.p. administration, its rapid distribution was observed ().

The anti-bacterial activity of berberine was evaluated () and cross resistance between berberine and antibiotics used in therapy was not observed. The anti-inflammatory effects of berberine were studied in rats injected locally with cholera toxin. This anti-inflammatory activity was also detected by several methods, e.g. fertile egg or cotton-pellet methods, by Otsuka et al. (). The hypotensive effect of berberine, followed by bradycardia, was observed in rats. This hypotensive effect may involve the depression of heart performance ().

Berberine displays weak cytotoxic activity on human and animal cell cultures in vitro (). Berberine administered orally prolonged the latent period and reduced the frequency of purging in dogs. Since it did not precipitate serum albumin or egg-white, its anti-diarrhoeal effect cannot be due to any astringent action (). The alkaloid inhibits electrogenic ion transport in rat isolated colon (). Berberine inhibits the formation of DNA, RNA, proteins and lipids. The inhibition of formation of macromolecules may reflect such primary actions as inhibition of glucose utilization and interaction with nucleic acids ().

Berberine (canadine, coptisine) inhibits the function of liver alcohol dehydrogenase (). Berberine was found to have an anti-secretory effect on rat ileum in vitro. This effect of mucosal berberine may be explained by stimulation of a NaCl-coupled absorptive transport process (). On the other hand, luminal berberine reduced the cholera toxin induced secretion of water, Na+ ions and Cl ions in a concentration-dependent manner in rat ileum (). Berberine also exhibits anti-malarial activity comparable to that of quinine in vitro ().

Berberine administered to rabbits anaesthetized with urethane produced a long-lasting dose-related decrease in blood pressure. This hypotensive effect of berberine was not influenced by vagotomy or pre-treatment with atropine. Berberine-induced hypotension is attributed to a-adrenoreceptor blockade, not a direct relaxant effect upon vascular smooth muscle ().

Coptisine

The anti-inflammatory activity of coptisine () was confirmed using the cotton-pellet method, the croton oil — granuloma pouch method, and the punch method. Antibacterial activity was also detected (). The binding of coptisine to DNA was studied (). This alkaloid inhibits acetylcholinesterase () and butyrylcholinesterase () enzymes in vitro.

Pharmacology of Poppy Alkaloids: Major Opium Alkaloids

 

Selections from the book: “Poppy. The Genus Papaver”. Edited by Jeno Bernáth. Series: “Medicinal and Aromatic Plants — Industrial Profiles”. 1998.