SYNTHESIS AND PHARMACOLOGY OF NOVEL ANTIDEPRESSANT AGENTS WITH DOPAMINE AUTORECEPTOR AGONIST PROPERTIES

摘要

To develop a novel antipsychotic agent which is an agonist of dopamine (DA) autoreceptors and an antagonist of postsynaptic DA receptors, a series of 2-[3-{4-(3-chlorophenyl)-1-piperazinyl} propyl]-1,2,4-triazolo [4,3-a] pyridine-3- (2H)-one hydrochloride was synthesized and their dual activities were examined. The reaction between 1, 2, 4-triazolo [4, 3-a] pyridine-3- (2H)-one and 1- (substituted-phenyl)-4-(3-halo-aryl) piperazine obtained from reaction of 1-(substituted-phenyl)-piperazine hydrochloride and dihalo- alkanes in two step process gave novel analogs of 2-[3-{4-(3-chlorophenyl)-1-piperazinyl} propyl]-1,2,4-triazolo [4,3-a] pyridine-3- (2H)- one hydrochloride has been achieved. These structures were established by IR, Mass and 1HNMR spectral data. The postsynaptic DA receptor antagonistic activities of the compounds were evaluated by their ability to inhibit stereotypy induced by apomorphine in mice, and the autoreceptor agonist activities were determined by their effects on the ?-butyrolactone (GBL) – induced increase in L- dihydroxyphenylalanine (DOPA) synthesis in the mouse brain. Many compounds inhibited the stereotypic behavior, and several compounds reversed the GBL induced increase in the DOPA synthesis.