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Effects of raubasine stereoisomers on pre- and postsynaptic α-adrenoceptors in the rat vas deferens
British Journal of Pharmacology
Abstract
The actions of raubasine, tetrahydroalstonine and akuammigine were studied on pre‐ and postsynaptic α‐adrenoceptors of the rat vas deferens.
These three drugs competitively antagonized the effect of noradrenaline on postsynaptic α‐adrenoceptors, yielding pA 2 values of 6.57, 4.56 and 4.68 respectively.
The presynaptic α‐adrenoceptor antagonist activity of the drugs was quantitatively determined by studying the effect of increasing concentrations on the clonidine dose‐response curve in the electrically stimulated vas deferens.
The inhibitory effect of clonidine could be competitively blocked by these three compounds and the pA 2 values for raubasine, tetrahydroalstonine and akuammigine were 6.02, 7.71 and 5.64 respectively.
These results indicate that: akuammigine is a very weak antagonist at pre‐ and postsynaptic sites; raubasine acts preferentially at postsynaptic sites; tetrahydroalstonine is a highly selective presynaptic α‐adrenoceptor blocking agent. The ratio of the pre/postsynaptic potency declines in the order tetrahydroalstonine > akuammigine > raubasine.
... The interaction of tetrahydroalstonine, an alkaloid closely related to alstonine, with the α-adrenergic receptors have been reported by Demichel and Roquebert (70). Raubasine, tetrahydroalstonine and akuammigine were shown to have inhibitory effects on sympathetic stimulation or adrenaline-induced hypertension, demonstrating specificity for presynaptic α2-adrenergic receptors (71). ...
Indole compounds, related to the metabolism of tryptophan, constitute an extensive family, and are found in bacteria, plants and animals. Indolic compounds possess significant and complex physiological roles, and especially indole alkaloids have historically constituted a class of major importance in the development of new plant derived drugs. The indole alkaloid alstonine has been identified as the major component of a plant-based remedy, used in Nigeria to treat mental illnesses by traditional psychiatrists. Although it is certainly difficult to compare the very concept of mental disorders in different cultures, the traditional use of alstonine is remarkably compatible with its profile in experimental animals. Even though alstonine in mice models shows a psychopharmacological profile closer to the newer atypical antipsychotic agents, it also shows important differences and what seems to be an exclusive mechanism of action, not entirely clarified at this point. Considering the seemingly unique mode of action of alstonine and that its traditional use can be viewed as indicative of bioavailability and safety, this review focuses on the effects of alstonine in the central nervous system, particularly on its unique profile as an antipsychotic agent. We suggest that a thorough understanding of traditional medical concepts of health and disease in general and traditional medical practices in particular, can lead to true innovation in paradigms of drug action and development. Overall, the study of this unique indole alkaloid may be considered as another example of the richness of medicinal plants and traditional medical systems in the discovery of new prototypic drugs.
Chinese herbal medicines (CHMs) are classified as dietary supplements. Interactions with western medications, the presence of contaminants or adulterants, or a mis-labeled or mis-used CHM may lead to toxicological emergencies that can be undetected in death investigations. Laboratories must be able to efficiently analyze cases in which CHMs are suspected. Five extractions were evaluated for their ability to extract pharmacologically active compounds from herbal matrices: water, ethanol, microwave-assisted (MAE), ethanol : chloroform, and acid-wash. Anticonvulsive and other pharmacologically active compounds in Gou Teng, Tian Ma, and Jiang Can purchased from Beijing, China and New York were compared in the powder and the extracts using Direct Analysis in Real Time-Mass Spectrometry (DART-MS). Approximately 0.25 g of macerated herb was used per extraction. The water and ethanol extractions were simple liquid extractions. For the MAE, powdered herb was soaked in 65% ethanol, microwaved, and concentrated. The ethanol : chloroform extraction involved soaking in 1 : 1 ethanol : chloroform, sonication, and concentration. In the acid-wash extraction, powdered herb was soaked in acetic acid, followed by addition of sodium hydroxide, hexane extraction, and reconstitution in ethyl acetate. The powdered herbs and extracts were analyzed using a Jeol JMS T100LC AccuTOF DART-MS in positive and negative mode. Of the evaluated methods, no single extraction worked for all active compounds from the three CHMs. The MAE extract contained the most pharmacologically active compounds, while the acid-wash contained the least for the three products. Gou Teng purchased from different sources did exhibit a difference in pharmacologically active compounds, potentially from different species.
A synthetic approach towards the core of a structurally unique cytotoxic indole alkaloid eleganine A has been accomplished for the first time. The synthesis features a stereoselective Ireland-Claisen rearrangement as...
The relative potencies of raubasine, tetrahydroalstonine (THA) and akuammigine on α1- and α2-adrenoceptors were assessed by comparing their effects on the rise in blood pressure induced by stimulation of the sympathetic outflow from the spinal cord or by injection of noradrenaline in pithed rats. Akuammigine was inactive in both cases. Raubasine preferentially antagonized the effects of electrical stimulation while THA antagonized the effects of injected noradrenaline. The results suggest that raubasine preferentially blocks α1-adrenoceptors while THA is more selective for α2-adrenoceptors.
Uncaria rhynchophylla (Miq.) Jacks, Rubiaceae, is one of the original plants of the important Chinese crude drug, Gou teng, mainly used for the treatment of convulsion, hypertension, epilepsy, eclampsia, and cerebral diseases. The pharmacological activities of this plant are related to the presence of active compounds predominantly indole alkaloids. In this article, we have reviewed some reports about the pharmacological activities of the main indole alkaloids isolated from U. rhynchophylla. This review paper will contribute to the studies on the chemistry, safety and quality control of medicinal preparations containing Uncaria species.
The single-crystal X-ray data of akuammigine picrate hydrate (1⋅Picr⋅H2O) confirm the relative configuration of the indole alkaloid akuammigine (1) as epiallo (Fig. 1). With reference to the known (15S)-configuration due to biosynthesis, the absolute configuration of the other stereogenic centers is thus given by (3R,19S,20S). Four crystallographically independent molecules are observed in the asymmetric unit (Fig. 2). Each of the alkaloid cations forms H-bonds to a H2O and a picrate anion (Fig. 3). The H2O molecules are further associated by a H-bond as indicated by the short O⋅⋅⋅O distance (Table 2). The conformation in the solid state of the picrate hydrate is now firmly established, and a cute H-bonding motif is observed.
The study examined the effects of R 47 243 and its (-)- and (+)-isomers as well as those of the putative α2-antagonists yohimbine, piperoxan, CGS 7225 A, and idazoxan at 1- to 24-hr time intervals after oral administration in rats. The experiments determined the antagonism produced by these compounds of the loss of the righting reflex (LRR) and of the exophthalmia (EXO) induced by intraperitoneal injection of 20 mg/kg of xylazine. Antagonism of LRR constitutes an in vivo measure of drug antagonist effects at CNS receptors that mediate behavioral depression produced by putative α2-agonists; antagonism of EXO offers an in vivo measure of α1-antagonist activity. More so than idazoxan or any of the other putative α2-antagonists tested, R 47 243 appeared to be a potent, long acting, and specific antagonist; it also acted as a full antagonist rather than as a partial agonist and showed excellent oral absorption.
The acid-catalysed epimerization reaction of bioactive indole alkaloids and their derivatives is reviewed. The three mechanisms, whichhave been proposed for the β-carboline-type indole alkaloids, are discussed. Through recent developments, evidence for all three mechanisms has been obtained, which shows the complexity of the epimerization reaction. The epimerization seems to depend on structural features and reaction conditions making it difficult to define one universal mechanism. On the other hand, the isomerization mechanism of oxindole alkaloids has been widely accepted. The acid-catalysed epimerization reaction provides a powerful tool in selectively manipulating the stereochemistry at the epimeric centre and it can also have a marked effect on the pharmacology of any epimerizable compound. Therefore, examples of this reaction in the total synthesis of indole alkaloids are given and pharmacological activities of some C-3 epimeric diastereomers are compared. Finally, literature examples of acid-catalysed epimerization reactions are presented.
A new method for quantification of electroencephalographic (EEG) signals was used to study the effects of almitrine and raubasine, alone and in combination, in two groups of six unanesthetized rats, aged 8 months (young) and 22 months (old). Coadministration of almitrine (7.5 mg/kg-1 i.p.) and raubasine (2.5 mg/kg-1 i.p.) induced an increased EEG power from 7 to 30 Hz; the frequencies concerned were identical in young and old rats, but the degree of their power variations was more marked in old rats. Almitrine induced a 20 to 50% increase in EEG power in young rats on nearly all spectral components. The effects of almitrine were only seen in the low-frequency range in old rats. Raubasine increased the EEG power in the 10 to 20 Hz frequency range; these effects were significantly greater in old rats. In both age groups, the effects on EEG power observed with coadministration of almitrine and raubasine were significantly different from those expected if raubasine and almitrine add their individual effects. These results show that a) almitrine and raubasine modify cortical electrical activity in a different manner as a function of age; b) the modification of the EEG activity induced by the coadministration is suggestive of an interaction between the cortical effects of each drug; and c) the modification of EEG power induced by the coadministration is qualitatively identical in young and old rats but quantitatively more marked in old rats.
The energy metabolism was evaluated in gastrocnemius muscle from 3-month-old rats subjected to either mild or severe 4-week intermittent normobaric hypoxia. Furthermore, 4-week treatment with CNS-acting drugs, namely, alpha-adrenergic (delta-yohimbine), vasodilator (papaverine, pinacidil), or oxygen-increasing (almitrine) agents was performed. The muscular concentration of the following metabolites was evaluated: glycogen, glucose, glucose 6-phosphate, pyruvate, lactate, lactate-to-pyruvate ratio; citrate, alpha-ketoglutarate, succinate, malate; aspartate, glutamate, alanine; ammonia; ATP, ADP, AMP, creatine phosphate. Furthermore the Vmax of the following muscular enzymes was evaluated: hexokinase, phosphofructokinase, pyruvate kinase, lactate dehydrogenase; citrate synthase, malate dehydrogenase; total NADH cytochrome c reductase; cytochrome oxidase. The adaptation to chronic intermittent normobaric mild or severe hypoxia induced alterations of the components in the anaerobic glycolytic pathway [as supported by the increased activity of lactate dehydrogenase and/or hexokinase, resulting in the decreased glycolytic substrate concentration consistent with the increased lactate production and lactate-to-pyruvate ratio] and in the mitochondrial mechanism [as supported by the decreased activity of malate dehydrogenase and/or citrate synthase resulting in the decreased concentration of some key components in the tricarboxylic acid cycle]. The effect of the concomitant pharmacological treatment suggests that the action of CNS-acting drugs could be also related to their direct influence on the muscular biochemical mechanisms linked to energy transduction.
The plasticity of synaptosomal non-mitochondrial ATPases was evaluated in cerebral cortex from 3-month-old normoxic rats and rats subjected to either mild or severe intermittent normobaric hypoxia [12 hr daily exposure to N2:O2 (90:10 or 91.5:8.5) for four weeks]. The activities of Na+, K(+)-ATPase, low- and high-affinity Ca(2+)-ATPase, Mg(2+)-ATPase, and Ca2+,Mg(2+)-ATPase were assayed in synaptosomes and synaptosomal subfractions, namely synaptosomal plasma membranes and synaptic vesicles. The evaluations were performed after a 4-week treatment with saline (controls) or alpha-adrenergic agents (delta-yohimbine, clonidine), a vasodilator compound (papaverine), and an oxygen-partial pressure increasing agent (almitrine). These treatments differently changed the adaptation to chronic intermittent hypoxia characterized by a decrease in the activity of Na+,K(+)-ATPase, Ca2+,Mg(2+)-ATPase, and high-affinity Ca(2+)-ATPase, concomitant with a modification in the activity of Mg(2+)-ATPase supported in a different way by the enzymatic forms located into the synaptosomal plasma membranes and synaptic vesicles.
Energy-using non-mitochondrial ATPases were assayed in rat cerebral cortex synaptosomes and synaptosomal subfractions, namely synaptosomal plasma membranes and synaptic vesicles. The following enzyme activities were evaluated: Na+, K+ -ATPase; high- and low-affinity Ca2+ -ATPase; basal Mg(2+)-ATPase; Ca2+, Mg(2+)-ATPase. The evaluations were performed after four week-treatment with saline [controls] or alpha-adrenergic agents (delta-yohimbine, clonidine), energy-metabolism interfering compound (theniloxazine), and oxygen-partial pressure increasing agent (almitrine), in order to define the plasticity and the selective changes in individual ATPases. In rat cerebral cortex, the enzyme adaptation to four-week-treatment with delta-yohimbine or clonidine was characterized by increase in both high- and low-affinity Ca2+ -ATPase activities. The action involves the enzyme form located in the synaptic plasma membranes. The enzyme adaptation to the subchronic treatments with theniloxazine or almitrine was characterized by increase in Na+, K(+)-ATPase or Mg(2+)-ATPase activities, respectively. The action involves the enzymatic forms located in the synaptic plasma membranes. Thus, the pharmacodynamic effects of the agents tested should also be related to the changes induced in the activity of some specific synaptosomal non-mitochondrial ATPases.
Extracts of the seeds of Picralima nitida (fam. Apocynaceae) have been reported to have opioid analgesic activity. In this investigation, isolated tissue bioassays and radioligand binding assays have been used to determine the opioid activity of five alkaloids--akuammidine, akuammine, akuammicine, akuammigine and pseudoakuammigine--extracted from the seeds of P. nitida. Akuammidine showed a preference for mu-opioid binding sites with Ki values of 0.6, 2.4 and 8.6 microM at mu-, delta- and kappa-opioid binding sites, respectively. The agonist actions of akuammidine in the mouse-isolated vas deferens were antagonised by naloxone and the mu-opioid receptor selective antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) confirming an action at mu-opioid receptors. In contrast, akuammine also showed highest affinity for mu-opioid binding sites (Ki 0.5 microM) but was an antagonist at mu-opioid receptors with a pK(B) of 5.7 against the selective mu-opioid receptor agonist [D-Ala2,MePhe4,Gly-ol5]enkephalin (DAMGO). Akuammicine has the highest affinity for kappa-opioid binding sites (Ki 0.2 microM) and was a full agonist at kappa-opioid receptors in the guinea pig ileum preparation but a partial kappa-opioid receptor agonist in the vasa deferentia of the mouse and the rabbit. Akuammigine and pseudoakuammigine showed little or no efficacy in the opioid bioassays. None of the alkaloids had significant activity for opioid receptor-like binding sites (ORL1-binding sites) with Ki values > 10 microM. These data show that some alkaloids extracted from the medicinal plant P. nitida possess varying degrees of agonist and antagonist activity at opioid receptors but possess neither high affinity nor selectivity for mu-, delta- or kappa-opioid receptors or the ORL1-receptor.
The influence of clonidine on presynaptic -adrenoceptors (mediating inhibition of noradrenaline release) and postsynaptic -adrenoceptors (mediating smooth muscle contraction) was compared in superfused strips of the rabbit pulmonary artery.1.
On smooth muscle -receptors, clonidine acted as a partial agonist. Its intrinsic activity was 0.32 of that of noradrenaline, the EC50 3.810–7 M, and the pA2 value of phentolamine against clonidine 7.56.
2.
The spontaneous outflow of tritium from arteries preincubated with 3H-noradrenaline was not changed by clonidine and phentolamine. Clonidine decreased, and phentolamine increased, tritium overflow evoked by transmural sympathetic nerve stimulation. The inhibition caused by clonidine was greater at a low (2 Hz) than at a high stimulation frequency (8 Hz). Phentolamine shifted the dose-response curve for clonidine to the right. The presence of noradrenaline in the biophase during stimulation complicated the calculation of drug-presynaptic receptor interaction constants; however, evidence is presented that the intrinsic activity of clonidine was similar to that of noradrenaline, its EC50 below 3.710–8 M, and the pA2 value of phentolamine against clonidine above 6.27.
3.
The combined contractile effect of low concentrations of clonidine (310–9 to 10–7 M) and of low frequencies of sympathetic nerve stimulation (0.25–2 Hz) was smaller than the effect of stimulation alone: the combined effect of low concentrations and high frequencies (4–32 Hz) did not differ from the effect of stimulation alone. The combined effect of 310–6 M clonidine and low frequencies of stimulation was greater, that of 310–6 M clonidine and high frequencies smaller than the effect of stimulation alone.
4.
In the rabbit pulmonary artery, the apparent affinity of clonidine to presynaptic -receptors is at least ten times higher than its apparent affinity to postsynaptic -receptors, probably because of differences in pre-and postsynaptic binding sites. When impulses reach noradrenergic nerve endings at physiological rates, low concentrations of clonidine, due to their preferential presynaptic effect, reduce overall postsynaptic adrenoceptor activation; the consequence is -sympathomimetic inhibition of neurogenic vasoconstriction.
The first clear statement of the principles of conformational analysis, as applied to cyclohexane derivatives, was made by Barton in 1950 (21). Since then conformational arguments have been invoked to deal with questions of relative stereochemistry throughout the whole realm of natural products. A previous review in this Series has discussed the application of conformational analysis to steroids and related natural products (24) and recently the numerous uses of this approach in the field of carbohydrate chemistry have been surveyed (61 a). The extension of conformational principles to nitrogen-containing molecules was an early development (43, 110), and alkaloids now constitute a great area of natural products which has been extensively investigated by the methods of conformational analysis.
The actions of raubasine, yohimbine and corynanthine at pre‐ and postsynaptic α‐adrenoceptors were studied in the rat vas deferens.
Low frequency electrical stimulation of the isolated vas deferens of the rat produced regular contractions that were inhibited by low concentrations of clonidine. This inhibition was presynaptic in origin and involved α‐adrenoceptors.
Presynaptic α‐adrenoceptor antagonist activity was assessed by studying the effect of increasing antagonist concentrations on cumulative clonidine dose‐response curves on the stimulated vas deferens.
Postsynaptic α‐adrenoceptor antagonist activity in the isolated vas deferens was assessed by comparing control cumulative noradrenaline dose‐response curves in the absence and in the presence of increasing concentrations of antagonists.
The results indicate that raubasine and corynanthine preferentially block postsynaptic α‐adrenoceptors. Yohimbine is more potent in blocking pre‐ than postsynaptic α‐adrenoceptors. The ratio of the pre/postsynaptic potency declines in the order yohimbine > raubasine > corynanthine.
1. The type and intensity of antagonism exerted by yohimbine and raubasine on the noradrenaline action have been studied in vitro. 2. Cumulative dose-response curves with noradrenaline as the agonist, were made using isolated thoracic aorta and vas deferens of rat kept in a Krebs solution. When an antagonist shift the curve to the right the competitive nature of the interaction was verified by assessing the regression straight line of log (x-I) on log (antagonist concentration) and calculation of pA2. 3. In rat isolated vas deferens, the isotonic contractile response to low doses of noradrenaline were antagonized and those to high does potentiated by raubasine. The alpha-adrenoceptor blocker thus caused a shift to the right and an increase of the maximum height of log dose-response curves of alpha-adrenoceptor stimulant. Yohimbine shift the dose-response curves to the right without change of maximal contraction. The curves were analysed with the Schhild plot, and the slopes obtained 0.82 (Yohimbine), 0.96 (Raubasine) were not significantly different from I. The pA2 value is of 6.10 for yohimbine and of 6.50 for raubasine. In the presence of cocaine, which blocks the neuronal uptake, the dose-response curves were shifted to the right in parallel without alteration of maximal contraction. The pA2 value is of 6.57 for yohimbine and of 6.75 for raubasine. Yohimbine and raubasine carry on a competitive type antagonism on the noradrenaline effect. 4. On the thoracic aorta, yohimbine (pA2 = 6.83) and raubasine (pA2 = 7.21) act as competitive antagonists.
The effects of prazosin on contractile responses of the epididymal and prostatic halves of the rat vas deferens have been studied. In the epididymal half responses to acetylcholine were not altered by hexamethonium, 100 microM, but were inhibited by atropine, 10 nM. Prazosin, 100 nM, had no effect on maximal or submaximal responses to acetylcholine or methacholine. In the presence of cocaine, 10 microM, prazosin 10 and 100 nM, reduced the magnitude of the maximal twitch and sustained responses to field stimulation in the epididymal and prostatic halves of the vas deferens. Submaximal responses at all frequencies of stimulation and to exogenously applied noradrenaline were also inhibited by prazosin. Thus all responses to field stimulation of the epididymal and prostatic halves of the vas deferens are susceptible to selective alpha 1-adrenoceptor blockade with low concentrations of prazosin.
The concept of two types of alpha-adrenoceptor, alpha 1 located on smooth muscle and mediating contraction and alpha 2 located on nerve terminals and mediating inhibition of transmitter release, has broken down. In vivo it has been shown that post-junctional receptors, with characteristics closely related to those of the alpha 2-adrenoceptors at nerve terminals, can mediate pressor responses and are, "post-junctional alpha 2-adrenoceptors". Several differences among agonists in vitro have superficial similarities to the in vivo alpha 1/alpha 2 system but do not correspond precisely and seem to point to a subdivision of post-junctional alpha 1-adrenoceptors. A preliminary hypothesis is: in vivo alpha 1 is rapid in onset, short-lived, utilises internal Ca2+, prefers alkalosis and responds to short-term stimuli such as short bursts of nerve impulses or bolus injections of catecholamines; alpha 2 is slower in onset, longer-lived, utilises external Ca2+, prefers acidosis and responds to more prolonged stimuli such as circulating catecholamines; in vitro these categories of response occur but antagonists fail to define an alpha 1/alpha 2 split, suggesting that some critical factor is missing in vitro. The implications of these trends in alpha-adrenoceptor classification are discussed in relation to current pharmacological and biochemical methods for receptor typing, to the possible physiological actions and roles of such receptors and to structure/activity relationships among agonists and antagonists.
Various applications of pA(x) measurements are discussed based on the hypothesis that drugs and drug antagonists compete for receptors according to the mass law. Examples are given illustrating the use of pA(x) measurements to identify agonists which act on the same receptors and to compare the receptors of different tissues. Tests of competitive and noncompetitive antagonism are considered in relation to the antagonisms acetylcholine-atropine, histamine-atropine and acetylcholine-cinchonidine. A new measure, pA(h), is introduced to express the activity of unsurmountable antagonists.
Toxicite et activit6 utero-adrenolytique d'une part de quelques ster6oisomeres de la yohimbine, d'autre part de la A-yohimbine ou raubasine
- X Rothlin
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Adrenolytische und sympthicolytische Wirkungen von Zwei neuen Rauwolfia Alkaloiden Raupin und Raubasin am Blutdruck and an Nickhaute der Katze
- G Achelis
KRONEBERG, G. & ACHELIS, J.D. (1954). Adrenolytische
und sympthicolytische Wirkungen von Zwei neuen
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270-273.
Pharmakologie des Rauwolfia Alkaloids Raubasin (A-yohimbine, ajmalicine) Archs exp
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Alkaloids Raubasin (A-yohimbine, ajmalicine). Archs
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Neue Alkaloide aus Rauwolfia Serpentina, pharmakologische Wirkungen
- J D Kroneberg
Comparison of the effects of clonidine on pre- and post-synaptic adrenoceptors in rabbit pulmonary artery. Nuanyn-Schmiedebergs Arch
- K Montel
- H Gayk
- W Merker
Toxicité et activité utéro-adrénolytique d'une part de quelques stéréoïsomères de la yohimbine, d'autre part de la Δ-yohimbine ou raubasine.
- RAYMOND-HAMET
Neue Alkaloide aus Rauwolfia Serpentina, pharmakologische Wirkungen.
- ACHELIS
Pharmakologie des Rauwolfia Alkaloids Raubasin (Δ-yohimbine, ajmalicine).
- KRONEBERG
Adrenolytische und sympthicolytische Wirkungen von Zwei neuen Rauwolfia Alkaloiden Raupin und Raubasin am Blutdruck and an Nickhaute der Katze.
- KRONEBERG G.
Comparison of the effects of clonidine on pre- and post-synaptic adrenoceptors in rabbit pulmonary artery.
- STARKE
Conformational analysis of some alkaloids.
- MORRISSON G.A.