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.
|Original language||English (US)|
|Number of pages||9|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - Jan 1 2006|
ASJC Scopus subject areas
- Molecular Medicine