RT Journal Article
SR Electronic
T1 Dual, Hyperalgesic, and Analgesic Effects of the High-Efficacy 5-Hydroxytryptamine 1A (5-HT1A) Agonist F 13640 [(3-Chloro-4-fluoro-phenyl)-[4-fluoro-4-{[(5-methyl-pyridin-2-ylmethyl)-amino]-methyl}piperidin-1-yl]methanone, Fumaric Acid Salt]: Relationship with 5-HT1A Receptor Occupancy and Kinetic Parameters
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1034
OP 1042
DO 10.1124/jpet.104.077669
VO 312
IS 3
A1 Laurent Bardin
A1 Marie-Bernadette Assié
A1 Martine Pélissou
A1 Isabelle Royer-Urios
A1 Adrian Newman-Tancredi
A1 Jean-Paul Ribet
A1 François Sautel
A1 Wouter Koek
A1 Francis C. Colpaert
YR 2005
UL http://jpet.aspetjournals.org/content/312/3/1034.abstract
AB The aim of the present study was to establish the relationship between the plasma and brain concentration-time profiles of F 13640 [(3-chloro-4-fluoro-phenyl)-[4-fluoro-4-{[(5-methyl-pyridin-2-ylmethyl)-amino]-methyl}piperidin-1-yl]methanone, fumaric acid salt] after acute administration and both its hyper- and hypoanalgesic effects in rats. The maximal plasma concentration (Cmax) of F 13640 after i.p. administration of 0.63 mg/kg was obtained at 15 min and decreased to half its maximal value after about 1 h. The amount of F 13640 collected by means of in vivo microdialysis in hippocampal dialysates could be measured reliably after 0.63 and 2.5 mg/kg, reached its maximum at about 1 h, and fell to half of its maximal value at about 3 h. 5-Hydroxytryptamine 1A (5-HT1A) receptor occupancy was estimated by ex vivo binding in rat brain sections. F 13640 inhibited [3H]8-hydroxy-2-[di-n-propylamino] tetralin binding ex vivo in rat hippocampus, entorhinal cortex, and frontal cortex (ED50, 0.34 mg/kg i.p.). Maximal inhibition was reached at approximately 30 min after 0.63 mg/kg F 13640 and fell to half of its value after about 4 to 8 h. After injection (15 min) in the paw pressure test, F 13640 (0.63 mg/kg i.p.) induced an initial hyperalgesia that was followed 4 h later by a paradoxical analgesia that lasted until 8 h. In contrast, in the formalin test, F 13640 inhibited pain behaviors until 4 h after drug administration. F 13640 also produced elements of the 5-HT syndrome that lasted up to 4 h after administration. These results demonstrate that F 13640 induces hyperalgesia and/or analgesia with a time course that parallels the occupancy of 5-HT1A receptors and the presence of the compound in blood and brain. The American Society for Pharmacology and Experimental Therapeutics