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NEUROPHARMACOLOGY

Dual, Hyperalgesic, and Analgesic Effects of the High-Efficacy 5-Hydroxytryptamine 1A (5-HT_1A) 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-HT_1A Receptor Occupancy and Kinetic Parameters

Centre de Recherche Pierre Fabre (L.B., M-.B.A., M.P., A.N.-T., J.-P.R., F.C.C.) and Preclinical DMPK Departement (I.R.-U., F.S.), Castres, France; and Alcohol and Drug Addiction Division, Department of Psychiatry, University of Texas Health Science Center, San Antonio, Texas (W.K.)

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 (C_max) 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-HT_1A) 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-HT_1A receptors and the presence of the compound in blood and brain.

Address correspondence to: Dr. Laurent Bardin, Department of General Pharmacology, Centre de Recherche Pierre Fabre, 17 avenue Jean Moulin, 81106 Castres Cedex. E-mail: laurent.bardin{at}pierre-fabre.com