Abstract
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-HT2C 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-HT2C 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-HT2C receptor inverse agonist). Taken together, these data show that the pharmacological characteristics of SB 243213 at the 5-HT2C 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.
Footnotes
-
This work was supported by National Institutes of Health Grant U.S. Public Health Service GM 56852 and grants from the National Alliance for Research on Schizophrenia and Depression, the Centre National de la Recherche Scientifique, and Bordeaux 2 University. S.N. was a fellowship recipient from the Ministère de la Recherche et de l'Enseignement Supérieur during the course of this study.
-
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
-
doi:10.1124/jpet.106.104448.
-
ABBREVIATIONS: 5-HT, 5,hydroxytryptamine, serotonin; 7-TMS, 7-transmembrane spanning; PLC, phospholipase C; IP, inositol phosphate; PLA2, phospholipase A2; AA, arachidonic acid; DOI, (±)-2,5-dimethoxy-4-iodoamphetamine hydrobromide; CHO, Chinese hamster ovary; SB 243213, 5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxyl]-5-pyridyl]carbamoyl]-6-trifluoromethylindone; SB206553, 5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f]indole; Ro 60-0175, S-2-(6-chloro-5-fluoroindol-1-yl)-1-methylethylamine; SB 242084, 6-chloro-5-methyl-1-[6-(2-methylpiridin-3-yloxy)pyridin-3-yl carbamoyl] indoline; DA, dopamine; NAc, nucleus accumbens; GTPγS, guanosine 5′-O-(3-thio)triphosphate; ANOVA, analysis of variance; PLSD, protected least significant difference; i.p., intraperitoneal.
- Received March 15, 2006.
- Accepted June 23, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|