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The decrease in locomotor activity in rats caused by alpha-methyldopa (alpha-MD), 400 mg/kg p.o. was antagonized by treatment with yohimbine, a selective antagonist of alpha 2-adrenoceptors. Effective doses of yohimbine ranged from 0.25--2.0 mg/kg s.c., whereas yohimbine at 0.125 mg/kg did not significantly affect the decrease in locomotor activity caused by alpha-MD. Similar results were obtained in studies on the interaction between clonidine injected intracisternally and various doses of yohimbine given s.c., except that the higher doses of yohimbine completely blocked the depression of locomotor activity caused by clonidine, but not by alpha-MD. The depression of motor activity following alpha-MD was not offset by prazosin, a preferential alpha 1-antagonist. At the same doses that failed to alter the action of alpha-MD, prazosin was effective in antagonizing the increase in motor activity resulting from intracisternally injected methoxamine, a selective agonist, at alpha 1-receptors. Treatment with FLA-63, using a regimen that was shown to inhibit dopamine-beta-hydroxylase in brain, caused a diminution in the ability of alpha-MD to depress locomotor activity. These findings indicate that alpha-MD reduces locomotor activity in the rat at least in part via the formation of alpha-methylnorepinephrine which acts on alpha 2-adrenoceptors.

In a study of nonsteroidal antiinflammatory and analgesic agents, a series of 1,3-dihydro-3-(substituted phenyl)imidazo[4,5-b]pyridin-2-ones-and 3-(substituted phenyl)triazolo[4,5-b]pyridines was prepared. Many of the imidazolones were alkylated on the free nitrogen. In a modified Randall-Selitto analgesic assay, the pain thresholds of both the inflamed and normal foot were elevated. This is not commonly observed with nonsteroidal antiinflammatory agents. The most active compounds were 1,3-dihydro-3[3,4-(methylenedioxy)phenyl]imidazo[4,5-b]pyridin-2-one (I-15) and its N-allyl (I-21) and N-isopropyl (I-121) derivatives. In the triazole series the 3-(2-fluoro- and 2,4-difluorophenyl)triazolo[4,5-b]pyridines (T-1 and T-8) were the best. The imidazole compounds were somewhat superior in analgesic activity to codeine and d-propoxyphene without showing any narcotic characteristics. Some of the compounds also possessed activity against carrageenan-induced foot edema in the rat, so these compounds represent a new class of nonnarcotic analgesic antiinflammatories, capable of producing a greater degree of analgesia than that obtainable with other nonsteroidal antiinflammatory agents.

Locomotor activity in rats was reduced by intracisternal (i.cis.) injection of the selective alpha 2-agonist clonidine and increased by the i.cis. administration of the selective alpha 1-agonists phenylephrine and methoxamine. These responses to i.cis. administered clonidine, phenylephrine and methoxamine were examined in rats pretreated subcutaneously (s.c.) with various alpha-adrenoceptor antagonists believed to exhibit preference for alpha 2- or alpha 1-receptors in peripheral tissues. At a dose that eliminated the locomotor depressant effect of clonidine, the alpha 2 -antagonist yohimbine did not antagonize the locomotor stimulant effects of phenylephrine and methoxamine. Similar results were obtained in animals pretreated with another alpha 2-antagonist piperoxane. The alpha 1-antagonist prazosin abolished the increase in motor activity elicited by phenylephrine and methoxamine, but at the same dose prazosin did not offset the decrease in motor activity caused by clonidine. The alpha 1-antagonist azapetine, at a dose that inhibited the increase in motor activity elicited by phenylephrine, was without effect on the decrease in activity produced by clonidine. These findings indicate that the locomotor responses to the alpha 2-agonist clonidine and the alpha 1-agonist phenylephrine (or methoxamine) can be used for determining whether or not a particular substance acts in vivo as a selective antagonist for alpha 1- or alpha 2-receptors in the CNS. In rats pretreated s.c. with 13.5 mg/kg of mianserin, the locomotor depressant effect of clonidine and stimulant action of phenylephrine were unchanged. At 27 mg/kg s.c., mianserin antagonized the responses to both clonidine and phenylephrine. Therefore, in this in vivo model system, mianserin given systemically did not display any appreciable selectivity for blocking alpha 1- or alpha 2-receptors in the CNS.

The synthesis and resolution of 3-iodocyproheptadine [(+/-)-5a] and 1-cyclopropylmethyl-4-(3-iodo-5H-dibenzo-[a,d]cyclohepten-5-ylidene)piperidine [(+/-)-5b] are described. The resulting atropisomers undergo reaction with trifluoromethylthiocopper to give optically active products without extensive racemization. In this manner, optically pure (+)- and (-)-3-trifluoromethylthiocyproheptadine [(+)-6a and (-)-6a, respectively] and (+)- and (-)-1-cyclopropylmethyl-4-(3-trifluoromethylthio-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine [(+)-6b and (-)-6b, respectively] have been prepared. The influence of a chiral europium shift reagent on the proton and fluorine resonance signals as a diagnostic tool for the determination of the optical purities of these atropisomers is discussed. The four compounds, (+)-6a, (-)-6a, (+)-6b, and (-)-6b, were studied in squirrel monkeys for their ability to block conditioned avoidance responding. All of the antiavoidance activity was found to reside solely in the levorotatory compounds (-)-6a and (-)-6b. Further comparison of the enantiomers (-)-6b and (+)-6b showed that the ability to antagonize apomorphine-induced stereotyped behavior is confined to the levorotatory isomer (-)-6b while weak central anticholinergic activity resides solely in the dextrorotatory isomer (+)-6b. Neither (-)-6b has significant peripheral anticholinergic activity.

A technique is described for measuring objectively and quantitatively the reaction of sensitized guinea pigs when exposed to an aerosol of specific antigen. The principle involves registration by semi-automatic means of the number of coughs produced in animals passively sensitized with known amounts of antibody. The number of coughs is shown to be linearly related to log dose of antibody within a limited range and a dose-response curve is presented. The cough produced by this procedure is not inhibited by the antitussive drugs, codeine and propadrine, but can be inhibited by anti-allergic agents, such as cortisone and an antihistaminic drug. It is also inhibited by narcotine. The last is the only compound so far tested which suppresses both the cough produced by this procedure and that produced by a simple irritant. The action of cortisone and the antihistaminic drug, pyrilamine, is shown to be synergistic. A small dose of pyrilamine in animals pretreated with cortisone gives a degree of inhibition which cannot be obtained by increasing the dose of pyrilamine in animals not treated with cortisone.