piperidines and 4-methyl-alpha-ethyl-m-tyramine

SR 95191 [3-(2-morpholino-ethyl-amino)-4-cyano-6-phenyl-pyridazine], a novel compound, has been shown in preliminary experiments to inhibit type A monoamine oxidase (MAO). This report describes the activities of SR 95191 in behavioral experiments in mice and rats and shows that SR 95191 has the profile of a selective type A MAO inhibitor (MAOI). Moreover, SR 95191 also possesses dopamine (DA) stimulant properties. The activities of SR 95191 were compared to those of the MAOIs moclobemide, clorgyline, pargyline and l-deprenyl, as well as to those of the antidepressant drugs imipramine, nomifensine and indalpine and to those of the DAergic drugs (+)-amphetamine and apomorphine. SR 95191 p.o. antagonized the effects of reserpine in mice and rats, decreased immobility in the mouse despair test, antagonized haloperidol-induced catalepsy in rats and potentiated 5-hydroxytryptophan in mice and rats with an overall potency which was half that of imipramine. SR 95191, like moclobemide, did not potentiate yohimbine-induced lethality and did not antagonize oxotremorine-induced tremor. Like selective type A MAOIs, SR 95191 potentiated 5-hydroxytryptophan-induced tremor without affecting beta-phenethylamine-induced stereotypies in mice. SR 95191 did not antagonize 3-hydroxy-4-methyl-alpha-phenylethylamine-induced hyperthermia. Like all DA stimulant drugs, SR 95191 induced stereotypies in rats, which were blocked by haloperidol and alpha-methylparatyrosine, and induced contralateral turning in mice with a unilateral striatal 6-hydroxydopamine lesion. Based on these results, it is postulated that SR 95191 has a unique profile of activity combining the properties of a selective type A MAO inhibitor and those of an atypical DAergic drug.

Topics: 5-Hydroxytryptophan; Amphetamines; Animals; Antidepressive Agents; Behavior, Animal; Benzamides; Body Temperature; Catalepsy; Clorgyline; Drug Interactions; Female; Haloperidol; Imipramine; Levodopa; Male; Mice; Moclobemide; Monoamine Oxidase Inhibitors; Motor Activity; Nomifensine; Oxotremorine; Pargyline; Piperidines; Pyridazines; Rats; Rats, Inbred Strains; Reserpine; Selegiline; Stereotyped Behavior

CGP 6085 A, [4-(5,6-dimethyl-2-benzofuranyl)piperidine HCl], has been found to be a mild to moderately potent hypotensive agent. One hour following CGP 6085 A administration (10 mg/kg, i.p.), a maximal reduction in blood pressure of approximately 20-30 mm Hg is observed in spontaneously hypertensive rats. The maximal reduction in blood pressure was observed at a dose of 3 mg/kg. CGP 6085 A blocks 5-HT uptake in the brainstem when assessed in vivo by use of the serotonin depletor, H 75/12 (3-hydroxy-4-methyl-alpha-ethyl-phenylethylamine). The maximal inhibitory effect on 5-HT uptake occurred at 10 mg/kg CGP 6085 A. The reduction in blood pressure correlates well with the ability of the drug to inhibit 5-HT uptake as assayed by H 75/12, with a correlation coefficient of 0.71 for SH rats. However, since the drug has not been widely characterized, alternate explanations for the cardiovascular pharmacological properties of CGP 6085 A are also proposed.

Topics: Amphetamines; Animals; Blood Pressure; Brain Stem; Heart Rate; Hydroxyindoleacetic Acid; Hypertension; Male; Nitroprusside; Piperidines; Rats; Rats, Inbred SHR; Serotonin

CGP 6085 A [4-(5,6-dimethyl-2-benzofuranyl) piperidine HCl], a reported serotonin uptake and MAO (16) inhibitor, is a potent hypothermic agent. The hypothermic action of CGP 6085 A is dose dependent with a maximal reduction in rectal core temperature of greater than 1 degree C within one hour after drug administration. Fluoxetine and citalopram elicit a similar response at equal doses. These results suggest that inhibition of serotonin uptake may produce the hypothermic effect. To assess the in vivo action of CGP 6085 A in inhibiting hypothalamic serotonin uptake, CGP 6085 A (10 mg/kg) was injected one hour prior to injection of 3-hydroxy-4-methyl-alpha-ethyl-phenylethylamine (H75/12), a serotonin depletor. The ability of CGP 6085 A to block the uptake of H75/12 by the 5HT uptake system was indicative of its ability to block serotonin uptake. Pretreatment with p-chlorophenylalanine (pCPA), an inhibitor of serotonin synthesis, resulted in the loss of the hypothermic response to CGP 6085 A. Thus, these data are consistent with the idea that CGP 6085 A may produce its hypothermic response by inhibiting serotonin uptake.

Topics: Amphetamines; Animals; Body Temperature; Dose-Response Relationship, Drug; Fenclonine; Hypothalamus; Kinetics; Male; Piperidines; Rats; Rats, Inbred Strains; Serotonin; Serotonin Antagonists