The International Journal of Neuropsychopharmacology

Research Article

F15599, a highly selective post-synaptic 5-HT1A receptor agonist: in-vivo profile in behavioural models of antidepressant and serotonergic activity

Marie-Bernadette Assiéa1, Laurent Bardina1, Agnès L. Auclaira1, Elisabeth Carilla-Duranda2, Ronan Depoortèrea1, Wouter Koeka1, Mark S. Klevena1, Francis Colpaerta3, Bernard Vachera4 and Adrian Newman-Tancredia1 c1

a1 Neurobiology II Division, Centre de Recherche Pierre Fabre, Castres, France

a2 ADME/Tox Department, Centre de Recherche Pierre Fabre, Castres, France

a3 Research Management, Centre de Recherche Pierre Fabre, Castres, France

a4 Medicinal Chemistry I Division, Centre de Recherche Pierre Fabre, Castres, France

Abstract

F15599 is a novel agonist with high selectivity and efficacy at serotonin 5-HT1A receptors (5-HT1ARs). In signal transduction, electrophysiological and neurochemical tests, F15599 preferentially activates post-synaptic 5-HT1ARs in rat frontal cortex. Such a profile may translate to an improved profile of therapeutic activity for mood disorders. The in-vivo effects of F15599 were therefore compared with those of a related compound, F13714, in rat models of antidepressant activity and 5-HT1AR activation: forced swimming test (FST), conditioned stress-induced ultrasonic vocalization, 5-HT syndrome, plasma corticosterone and body temperature. Acute administration of F15599 or F13714 reduced immobility in the FST at low doses; these effects were long lasting and the effects of F15599 were maintained after repeated (5 d, p.o.) administration. Both compounds decreased ultrasonic vocalization duration at low doses. In contrast, higher doses of F15599 were required to induce lower lip retraction, elements of the 5-HT behavioural syndrome, hypothermia and to increase plasma corticosterone levels. Notably, there was a greater separation of ED50 between FST and other effects for F15599 than for F13714. Thus, the in-vivo potency of F15599 in models of antidepressant/anti-stress activity is similar to that of F13714, despite the fact that the latter has an in-vitro potency two orders of magnitude greater. In contrast F15599 has a lower propensity than F13714 to induce other serotonergic signs. The distinctive pharmacological profile of F15599 suggests that preferential targeting of post-synaptic 5-HT1ARs constitutes a promising strategy for improved antidepressant therapy.

(Received August 19 2009)

(Revised November 19 2009)

(Accepted December 01 2009)

(Online publication January 11 2010)

Correspondence:

c1 Address for correspondence: Dr A. Newman-Tancredi, Neurobiology II Division, Centre de Recherche Pierre Fabre, 17 avenue Jean Moulin, 81106 Castres Cedex, France. Tel.: +33563 714 269 Fax: +33 563 714 363 Email: adrian.newman.tancredi@pierre-fabre.com

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