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CELLULAR AND MOLECULAR

Differential Effects of 5-Methyl-1-[[2-[(2-methyl-3-pyridyl)oxyl]-5-pyridyl]carbamoyl]-6-trifluoromethylindone (SB 243213) on 5-Hydroxytryptamine_2C Receptor-Mediated Responses

Department of Pharmacology, University of Texas Health Science Center, San Antonio, Texas (K.A.B., T.A.S., Y.M.S., W.P.C.); Unité Mixte de Recherche-Centre National de la Recherche Scientifique 5541, Université Victor Segalen Bordeaux 2, Bordeaux Cedex, France (S.N., U.S.); and Neuropharmacology Research, Psychiatry CEDD, GlaxoSmithKline, Harlow, United Kingdom (M.D.W.)

5-Methyl-1-[[2-[(2-methyl-3-pyridyl)oxyl]-5-pyridyl]carbamoyl]-6-trifluoromethylindone (SB 243213) is a selective, high-affinity 5-hydroxytryptamine (serotonin)_2C receptor ligand that has been previously characterized as a competitive 5-HT_2C receptor antagonist that has a long duration of activity in vivo. It is active in two preclinical models of anxiety and has an improved anxiolytic profile compared with benzodiazepines. In this study, we further characterized the pharmacological properties of SB 243213 by measuring its effects on each of multiple responses coupled to the 5-HT_2C receptor. In Chinese hamster ovary cells, SB 243213 was an inverse agonist for the phospholipase A₂ response, for guanosine 5'-O-(3-[³⁵S]thio)triphosphate binding, for reduction of constitutive desensitization, and for enhancement of dopamine release in the rat nucleus accumbens, with relative efficacies of 0.6, 1, 1, and 0.6, respectively. However, for the phospholipase C (PLC) signaling cascade, SB 243213 behaved as an antagonist. Although SB 243213 was previously characterized as a competitive antagonist for the PLC response, the magnitude of the dextral shift of the 5-HT concentration-response curve was time-dependent, and the maximal PLC response to 5-HT was decreased, probably as a result of the slow dissociation rate of SB 243213 (initial dissociation rate was 3.2 times slower than SB206553, a prototypical 5-HT_2C receptor inverse agonist). Taken together, these data show that the pharmacological characteristics of SB 243213 at the 5-HT_2C receptor differ depending upon the response measured, and they support the hypothesis that different drugs, acting at the same receptor subtype, can differentially regulate multiple cellular signaling systems.

Address correspondence to: Dr. Kelly A. Berg, Department of Pharmacology, 7703 Floyd Curl Dr., San Antonio, TX 78229-3900. E-mail: berg{at}uthscsa.edu

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