US EPA

1491468 

Journal Article 

Efficacy of selective 5-HT6 receptor ligands determined by monitoring 5-HT6 receptor-mediated cAMP signaling pathways 

Romero, G; Sanchez, E; Pujol, M; Perez, P; Codony, X; Holenz, J; Buschmann, H; Pauwels, PJ 

2006 

Yes 

British Journal of Pharmacology
ISSN: 0007-1188
EISSN: 1476-5381 

148 

8 

1133-1143 

English 

16865095 

10.1038/sj.bjp.0706827 

WOS:000239758900013 

http://://WOS:000239758900013
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1 Two novel selective 5-HT6 receptor ligands E-6801 (6-chloro-N-(3-(2-(dimethylamino)ethyl)-1H-indol-5- yl) imidazo[2,1-b]thiazole-5-sulfonamide) and E-6837 (5-chloro-N-(3-(2-(dimethylamino)ethyl)1H-indol-5-yl) naphthalene-2-sulfonamide) were investigated and compared to the putative 5-HT6 receptor antagonists SB-271046 (5-chloro-N-(4-methoxy-3-(piperazin-1-yl)phenyl)-3-methylbenzo[b] thiophene-2-sulfonamide) and Ro 04-06790 (N-(2,6-bis(methylamino)pyrimidin-4-yl)-4-aminobenzenesulfonamide) using a cAMP-mediated pathway. 2 Forskolin stimulation, to increase the magnitude of agonist cAMP responses, and site-directed mutagenesis of the 5-HT6 receptor, in order to yield constitutively active receptor, were applied. 3 5-HT (E-max, % over basal: 200), E-6801 (120) and E-6837 (23) induced cAMP formation at the rat 5-HT6 receptor. In the copresence of forskolin, cAMP responses were more potent and enhanced to 294 (5-HT, % over forskolin), 250 (E-6801) and 207 (E-6837), respectively. 5-HT-mediated cAMP formation was dose-dependently blocked by SB-271046 (pA(2): 8.76 +/- 0.22) and Ro 04-6790 (pA(2): 7.89 +/- 0.10) and not affected by the copresence of forskolin. Both E-6801 and E-6837 yielded partial antagonism of the 5-HT response in the absence of forskolin, whereas antagonism was either completely absent (E-6801) or attenuated (E-6837) in the copresence of forskolin. Intrinsic activity of these 5-HT6 receptor ligands at a constitutively active human S267K 5-HT6 receptor in Cos-7 cells indicated similar efficacy (E-max, % over basal) for 5-HT (97), E-6801 (91) and E-6837 (100), while Ro 04-6790 (-33) and SB-271046 (-39) were equi-efficacious inverse agonists. 4 The use of either forskolin or a constitutively active S267K 5-HT6 receptor enhances the resolution for monitoring the efficacy of 5-HT6 receptor ligands. E-6801 and E-6837 are potent partial agonists at the 5-HT6 receptor. Ro 04-6790 and SB-271046 appear to act as inverse agonists/antagonists. 

5-HT6 receptor; ligand efficacy; constitutive activation; adenylyl cyclase; cyclic-AMP (cAMP); partial agonist; inverse agonist; HEK-293F and Cos-7 cells