Research article summary (published 18 Mar 2007):

F15063, a compound with D2/D3 antagonist, 5-HT 1A agonist and D4 partial agonist properties. II. Activity in models of positive symptoms of schizophrenia.

Full Abstract

BACKGROUND AND PURPOSE: F15063 is a high affinity D(2)/D(3) antagonist, D(4) partial agonist, and high efficacy 5-HT(1A) agonist, with little affinity (40-fold lower than for D(2) receptors) at other central targets. Here, the profile of F15063 was evaluated in models of positive symptoms of schizophrenia and motor side-effects. EXPERIMENTAL APPROACH: Rodent behavioural tests were based on reversal of hyperactivity induced by psychostimulants and on measures of induction of catalepsy and 'serotonin syndrome'. KEY RESULTS: F15063 potently (ED(50)s: 0.23 to 1.10 mg kg(-1) i.p.) reversed methylphenidate-induced stereotyped behaviors, blocked d-amphetamine and ketamine hyperlocomotion, attenuated apomorphine-induced prepulse inhibition (PPI) deficits, and was active in the conditioned avoidance test. In mice, it reversed apomorphine-induced climbing (ED(50)=0.30 mg kg(-1) i.p.). F15063, owing to its 5-HT(1A) agonism, did not produce (ED(50)>40 mg kg(-1) i.p.) catalepsy in rats and mice, a behavior predictive of occurrence of extra-pyramidal syndrome (EPS) in man. This absence of cataleptogenic activity was maintained upon sub-chronic treatment of rats for 5 days at 40 mg kg(-1) p.o. Furthermore, F15063 did not induce the 'serotonin syndrome' in rats (flat body posture and forepaw treading: ED(50) >32 mg kg(-1) i.p.). CONCLUSIONS AND IMPLICATIONS: F15063 conformed to the profile of an atypical antipsychotic, with potent actions in models of hyperdopaminergic activity but without inducing catalepsy. These data suggest that F15063 may display potent antipsychotic actions with low EPS liability. This profile is complemented by a favourable profile in rodent models of negative symptoms and cognitive deficits of schizophrenia (companion paper).

Author information

Author/s: Depoortère, R (R); Bardin, L (L); Auclair, A L (AL); Kleven, M S (MS); Prinssen, E (E); Colpaert, F (F); Vacher, B (B); Newman-Tancredi, A (A);

Affiliation: Division of Neurobiology 2, Centre de Recherche Pierre Fabre, Castres, France. ronan.depoortere(-atsign-)pierre-fabre.com

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: British journal of pharmacology (Br J Pharmacol), published in England. (Language: eng)

Reference: 2007-May; vol 151 (issue 2) : pp 253-65

Dates: Created 2007/05/14; Completed 2007/08/07; Revised 2008/11/20;

PMID: 17375086, status: MEDLINE (last retrieval date: 2/18/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

Comments and Corrections

CommentIn: Br J Pharmacol. 2007 May;151(2):161-2. (PMID: 17375084)

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Animals Antipsychotic Agents - pharmacology Behavior, Animal - drug effects Benzofurans - pharmacology Benzylamines - pharmacology Cyclopentanes - pharmacology Dopamine Agonists - pharmacology Dopamine Antagonists - pharmacology Dose-Response Relationship, Drug Drug Interactions Male Mice Mice, Inbred Strains Models, Animal Motor Activity - drug effects

Motor Activity - drug effects Piperazines - pharmacology Prolactin - blood Pyridines - pharmacology Rats Rats, Sprague-Dawley Receptor, Serotonin, 5-HT1A - agonists; antagonists & inhibitors Receptors, Dopamine D2 - antagonists & inhibitors Receptors, Dopamine D3 - antagonists & inhibitors Receptors, Dopamine D4 - agonists Schizophrenia - physiopathology; prevention & control Serotonin Agonists - pharmacology Serotonin Antagonists - pharmacology Startle Reaction - drug effects Treatment Outcome

Associated Chemicals: Antipsychotic Agents (0) ; Benzofurans (0) ; Benzylamines (0) ; Cyclopentanes (0) ; Dopamine Agonists (0) ; Dopamine Antagonists (0) ; N-((2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)ethyl)-3-(cyclopent-1-enyl)-benzylamine (0) ; Piperazines (0) ; Pyridines (0) ; Receptors, Dopamine D2 (0) ; Receptors, Dopamine D3 (0) ; Serotonin Agonists (0) ; Serotonin Antagonists (0) ; Receptor, Serotonin, 5-HT1A (112692-38-3) ; Receptors, Dopamine D4 (137750-34-6) ; WAY 100635 (146714-97-8) ; Prolactin (9002-62-4)

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