title: Activity of aromatic substituted phenylpiperazines lacking affinity for dopamine binding sites in a preclinical test of antipsychotic efficacy.
abstract: Generally, antipsychotic agents are dopamine receptor blocking agents that also block conditioned avoidance responding (CAR) in the rat. Recently, however, both (Q-methoxyphenyl)piperazine (OMPP, 1h) and (m-chlorophenyl)piperazine (MCPP, 1o) have been reported to block conditioned avoidance responding in the rat although neither has dopamine receptor blocking properties. The present paper examines the behavioral and biochemical profile of a number of additional substituted phenylpiperazines. None of the phenylpiperazines tested demonstrated high affinity for either dopamine D-1 or D-2 receptor sites, yet many were effective in blocking CAR. The results suggest that the phenylpiperazines may be effective antipsychotic agents without blocking dopamine receptors. Moreover, the active compounds did demonstrate activity in displacing ligand binding to serotonin receptors. Receptor binding profiles were determined for 5-HT-1A and 5-HT-1B binding sites as well as for 5-HT-2 sites. The data from this preclinical test suggest these phenylpiperazines might be effective antipsychotic agents acting via a nondopaminergic mechanism of action.
authors.affiliation: Department of Biological Research, McNeil Pharmaceutical and Janssen Research Foundation Worldwide, Spring House, Pennsylvania 19477.
authors.forename: G E
authors.initials: GE
authors.lastname: Martin
authors.forename: R J
authors.initials: RJ
authors.lastname: Elgin
authors.forename: J R
authors.initials: JR
authors.lastname: Mathiasen
authors.forename: C B
authors.initials: CB
authors.lastname: Davis
authors.forename: J M
authors.initials: JM
authors.lastname: Kesslick
authors.forename: W J
authors.initials: WJ
authors.lastname: Baldy
authors.forename: R P
authors.initials: RP
authors.lastname: Shank
authors.forename: D L
authors.initials: DL
authors.lastname: DiStefano
authors.forename: C L
authors.initials: CL
authors.lastname: Fedde
authors.forename: M K
authors.initials: MK
authors.lastname: Scott
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D011954:Receptors, Dopamine / Q000187:drug effects*; D011985:Receptors, Serotonin / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D014150:Antipsychotic Agents; D010879:Piperazines; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; C031503:phenylpiperazine