MIXED 5-HT1A D-2 ACTIVITY OF A NEW MODEL OF ARYLPIPERAZINES - 1-ARYL-4-[3-(1,2-DIHYDRONAPHTHALEN-4-YL)-N-PROPYL] .1. SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS/

A new model of 4-alkyl-1-arylpiperazines containing a terminal dihydro naphthalene fragment on the alkyl chain was synthesized in order to ha ve mixed serotonergic and dopaminergic activity and to pursue the rece nt alternative approaches to the discovery of novel antipsychotic and anxiolytic agents. Title compounds were evaluated for in vitro activit y on dopamine D-2 and serotonin 5-HT1A and 5-HT2 receptors by radiorec eptor binding assays. They show high nanomolar affinity for 5-HT1A mod erate affinity for D-2, and low affinity for 5-HT2 receptors, and in p articular, two compounds, 3-(1,2-dihydro-6-methoxynaphthalen-4-yl)-n-p ropyl] 1-(2-methoxyphenyl)piperazine (8) and naphthalen-4-yl)-n-propyl ]-1-(2-pyridyl)piperazine (15), show values (nM) of IC50 = 2.0 and 1.4 for 5-HT1A and IC50 = 90.6 and 119.3 for D-2, respectively. Some in v ivo behavioral studies show compound 8 to be an antagonist on 5-HT1A r eceptors. These first findings place the new arylpiperazines on the sa me level as that of the azaspirone class, oxyphenyl)-4-[4-(2-phthalimi do)-n-butyl]piperazine (NAN-190) and buspirone.