A pharmacological study of two bisbenzylisoquinoline alkaloids, thalistyline and obamegine.

Thalistyline, a monoquaternary bisbenzylisoquinoline alkaloid isolated from Thalictrum sp. inhibited respiration in anesthetized dogs. Thalistyline is about one-fourth as potent as d-tubocurarine in blocking neuromuscular transmission in the rat hemidiaphragm preparation. The pharmacological mechanism of action of the alkaloid is similar to that of d-tubocurarine. Obamegine did not exhibit curare-like activity. On the isolated rabbit aorta, contractions induced by an alpha-adrenoreceptor agonist, phenylephrine, were antagonized by both alkaloids. Increasing concentrations of thalistyline produced parallel shifts to the right in the dose-response curves of phenylephrine. The pA2 value for the competitive pharmacological antagonism was 6.33. Obamegine also antagonized the effects of phenylephrine on the aorta, line and obamegine lowered blood pressure in normotensive dogs. The effect was transient. Repeated injections of the alkaloids resulted in tachyphylaxis to blood pressure lowering effects. Although alkaloids exhibited alpha adrenergic blockade in the vascular preparation, the mechanism for the hypotensive effect remains to be established.

Alkaloids of Thalictrum. XV. Isolation and identification of the hypotensive alkaloids of the root of Thalictrum lucidum.

Sixteen alkaloids, namely homoaromoline, obaberine, O-methyl-thalicberine, oxyberberine, thalidasine, thaliglucinone, thalrugosine, obamegine, oxyacanthine, berberine, columbamine, jatrorrhizine, magnoflorine, palmatine, thalifendine and base A chloride, plus the artifact, 8-trichloromethyldihydroberberine, were isolated from the alkaloid fraction of the roots of Thalictrum lucidum L. Of these, obamegine, thalrugosine, O-methylthalicberine, thaliglucinone, obaberine and homoaromoline were found to possess hypotensive activity in normotensive dogs. Thalidasine, homoaromoline, thalrugosine, thaliglucinone, obamegine, jatrorrhizine, and columbamine were found to possess antimicrobial activity against Mycobacterium smegmatis at a concentration of 100 mug/ml or less.

Conformationally defined adrenergic agents I: potentiation of levarterenol in rat vas deferens by endo- and exo- 2- aminobenzobicyclo[2.2.2]octenes, conformationally defined analogs of amphetamine.

Four conformationally defined analogs of amphetamine were synthesized and studied for their ability to potentiate the action of levarterenol on the isolated vas deferens from reserpine-treated rats. The compunds also were studied for indirect adrenergic agonist activity in the same test system. A definite stereochemical correlation was demonstrated in each case, the exo-isomers being considerably more active than their endo-counterparts both in potentiation and in indirect activity. The more active isomers of each pair correspond to an anti-periplanar conformation of amphetamine. The compounds are probably acting by inhibition of the neuronal amine uptake mechanism, since none of the compounds was a direct-acting agonist itself. These results are discussed in relationship to other previously reported, conformationally defined, amphetamine analogs.

Influence of group selective reagents in tissues containing alpha- and beta-adrenoceptors.

N-ethylmaleimide which is known to react irreversibly with free -SH groups of protein when incubated with rabbit aorta (alpha-adrenoreceptor) or atria (beta-adrenoreceptor) markedly depressed the dose-response curves of norepinephrine isomers in the aorta but not in atria. Dithiothreitol, a reagent which reduces S-S linkages caused a parallel shift of the dose-response curves of both isomers to an equal degree in aorta. However, in atria the reagent drastically and selectively reduced the maximal effects of (+)-norepinephrine and dopamine. This selective alteration of the (+)-isomer by the reagent probably reflects the conformational changes at the beta-adrenoreceptor. The concentrations of N-ethylmaleimide and dithiothreitol required to alter the activity of norepinephrine isomers was higher for atria than for aorta. It may be that alpha-adrenoreceptors are more susceptible than the beta-adrenoreceptors on the -SH group selective reagents. In the highest concentration tested, two other reagents 2,4-dimethoxybenzylamine and N-acetylimidazole, did not influence the activity of the steroisomers on aorta. In the presence of dithiothreitol, the pharmacologic effects of a nonadrenoreceptor stimulant drug, histamine was potentiated on aorta (H1) and not on atria (H2). Results are discussed in the light of similarity and dissimilarity of adrenoreceptors as reflected by the group selective reagents and the stereoisomers.

Importance of the aromatic ring in adrenergic amines. 2. Synthesis and adrenergic activity of some nonaromatic six- and eight-membered ring analogs of beta-phenylethanolamine.

The synthesis of beta-phenylethanolamine analogs in which the phenyl ring is replaced by cyclohexyl, cyclohexen-4-yl, cyclooctyl, cyclooctenyl, cycloocta-1,3-dien-2-yl, cycloocta-1,5-dienyl, and cyclooctatetraenyl was accompanied by conversion of the corresponding aldehydes to the cyanohydrins followed by reduction with lithium aluminum hydride. A preparatively useful synthesis of 1-formylcyclooctatetraene is described utilizing the photocycloaddition of methyl propiolate to benzene followed by reduction to the alcohol and oxidation with MnO2. All compounds, as their hydrochloride salts, exhibited indirect adrenergic activity on the rat vas deferens. On the reserpinized rat vas deferens all compounds potentiated the effects of exogenous norepinephrine. The results are in agreement with the conclusion that the more saturated the ring moiety, the greater the affinity for the amine uptake site of the vas deferens and suggest that there is no important interaction between the drug and this uptake site that involves pi-complex formation.