F15599, a highly selective post-synaptic 5-HT(1A) receptor agonist: in-vivo profile in behavioural models of antidepressant and serotonergic activity.
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.
Assié
Marie-Bernadette
MB
Neurobiology II Division, Centre de Recherche Pierre Fabre, Castres, France.
Bardin
Laurent
L
Auclair
Agnès L
AL
Carilla-Durand
Elisabeth
E
Depoortère
Ronan
R
Koek
Wouter
W
Kleven
Mark S
MS
Colpaert
Francis
F
Vacher
Bernard
B
Newman-Tancredi
Adrian
A
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
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