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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on June 28, 2006; DOI: 10.1124/jpet.106.104448

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Received for publication March 15, 2006.
Revised June 23, 2006.
Accepted for publication June 23, 2006.

Differential Effects of SB 243213 on 5 HT2C Receptor-Mediated Responses

Kelly A. Berg 1*, Sylvia Navailles 2, Teresa A. Sanchez 3, Yamille M. Silva 1, Martyn D. Wood 4, Umberto Spampinato 2, William P. Clarke 1

1 University of Texas Health Science Center 2 Universite Victor Segalen Bordeaux 2 3 university of Texas Health Science Center 4 GlaxoSmithKline

* Address correspondence to: E-mail: berg{at}uthscsa.edu

Abstract

SB 243213 is a selective, high affinity serotonin2C (5 HT2C) receptor ligand that has been previously characterized as a competitive 5 HT2C receptor antagonist which has a long duration of activity in vivo. It is active in two pre-clinical models of anxiety and has an improved anxiolytic profile compared to 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 CHO cells, SB 243213 was an inverse agonist for the phospholipase A2 (PLA2) response, for GTP[{gamma}35S] binding, for reduction of constitutive desensitization and for enhancement of dopamine (DA) release in the rat nucleus accumbens, with relative efficacies of 0.6, 1, 1 and 0.6, respectively. However, for the 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 serotonin (5 HT) concentration-response curve was time dependent and the maximal PLC response to 5 HT was decreased, likely as a result of the slow dissociation rate of SB 243213 (initial dissociation rate was 3.2 times slower than SB 206553, 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 support the hypothesis that different drugs, acting at the same receptor subtype, can differentially regulate multiple cellular signaling systems.


Key words: agonist-directed trafficking of receptor stimulus, antagonist, dopamine, efficacy, inverse agonist, microdialysis


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Pharmacol. Rev., December 1, 2007; 59(4): 360 - 417.
[Abstract] [Full Text] [PDF]


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