title: F15599, a highly selective post-synaptic 5-HT(1A) receptor agonist: in-vivo profile in behavioural models of antidepressant and serotonergic activity.
abstract: F15599 is a novel agonist with high selectivity and efficacy at serotonin 5-HT(1A) receptors (5-HT(1A)Rs). In signal transduction, electrophysiological and neurochemical tests, F15599 preferentially activates post-synaptic 5-HT(1A)Rs 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-HT(1A)R 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-HT(1A)Rs constitutes a promising strategy for improved antidepressant therapy.
authors.affiliation: Neurobiology II Division, Centre de Recherche Pierre Fabre, Castres, France.
authors.forename: Marie-Bernadette
authors.initials: MB
authors.lastname: Assié
authors.forename: Laurent
authors.initials: L
authors.lastname: Bardin
authors.forename: Agnès L
authors.initials: AL
authors.lastname: Auclair
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Carilla-Durand
authors.forename: Ronan
authors.initials: R
authors.lastname: Depoortère
authors.forename: Wouter
authors.initials: W
authors.lastname: Koek
authors.forename: Mark S
authors.initials: MS
authors.lastname: Kleven
authors.forename: Francis
authors.initials: F
authors.lastname: Colpaert
authors.forename: Bernard
authors.initials: B
authors.lastname: Vacher
authors.forename: Adrian
authors.initials: A
authors.lastname: Newman-Tancredi
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D003345:Corticosterone / Q000097:blood / Q000378:metabolism; D003863:Depression / Q000188:drug therapy*; D007035:Hypothermia / Q000139:chemically induced; D008297:Male; D023421:Models, Animal; D058990:Molecular Targeted Therapy; D009043:Motor Activity / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D017397:Prefrontal Cortex / Q000187:drug effects; D011743:Pyrimidines / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012701:Serotonin / Q000494:pharmacology; D058825:Serotonin 5-HT1 Receptor Agonists / Q000627:therapeutic use*; D013312:Stress, Physiological / Q000187:drug effects; D013550:Swimming / Q000502:physiology
chemical_list: C119079:3-chloro-4-fluorophenyl-(4-fluoro-4-(((5-methyl-6-methylaminopyridin-2-ylmethyl)amino)methyl)piperidin-1-yl)methanone; C524188:3-chloro-4-fluorophenyl-(4-fluoro-4-(((5-methylpyrimidin-2-ylmethyl)amino)methyl)piperidin-1-yl)methanone; D000631:Aminopyridines; D000928:Antidepressive Agents; D010880:Piperidines; D011743:Pyrimidines; D058825:Serotonin 5-HT1 Receptor Agonists; D012701:Serotonin; D003345:Corticosterone