Mixed 5-HT1A/D-2 Activity of a New Model of Arylpiperazines: 1-Aryl-4-piperazines. 1. Synthesis and Structure-Activity Relationships

Article abstract of DOI:10.1021/jm00027a012

A new model of 4-alkyl-1-arylpiperazines containing a terminal dihydronaphthalene fragment on the alkyl chain was synthesized in order to have mixed serotonergic and dopaminergic activity and to persue the recent alternative approaches to the discovery of novel antipsychotic and anxiolytic agents.Title compounds were evaluated for in vitro activity on dopamine D-2 and serotonin 5-HT_1A and 5-HT₂ receptors by radioreceptor binding assays.They show high nanomolar affinity for 5-HT_1A, moderate affinity for D-2, and low affinity for 5-HT₂ receptors, and in particular, two compounds, 4-<3-(1,2-dihydro-6-methoxynaphthalen-4-yl)-n-propyl>-1-(2-methoxyphenyl)piperazine (8) and 4-<3-(1,2-dihydro-8-methoxynaphthalen-4-yl)-n-propyl>-1-(2-pyridyl)piperazine (15), show values (nM) of IC₅₀ = 2.0 and 1.4 for 5-HT_1A and IC₅₀ = 90.6 and 119.3 for D-2, respectively.Some in vivo behavioral studies show compound 8 to be an antagonist on 5-HT_1A receptors.These first findings place the new arylpiperazines on the same level as that of the azaspirone class, e.g., 1-(2-methoxyphenyl)-4-<4-(2-phthalimido)-n-butyl>piperazine (NAN-190) and buspirone.