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Efficacy of selective 5‐HT6 receptor ligands determined by monitoring 5‐HT6 receptor‐mediated cAMP signaling pathways
Author(s) -
Romero Gonzalo,
Sánchez Elisabeth,
Pujol Marta,
Pérez Pilar,
Codony Xavier,
Holenz Jörg,
Buschmann Helmut,
Pauwels Petrus J
Publication year - 2006
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0706827
Subject(s) - forskolin , antagonism , receptor , agonist , chemistry , sulfonamide , pharmacology , stereochemistry , medicine , biology , biochemistry
1 Two novel selective 5‐HT6 receptor ligands E‐6801 (6‐chloro‐ N ‐(3‐(2‐(dimethylamino)ethyl)‐1 H ‐indol‐5‐yl)imidazo[2,1‐ b ]thiazole‐5‐sulfonamide) and E‐6837 (5‐chloro‐ N ‐(3‐(2‐(dimethylamino)ethyl)‐1 H ‐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 ( p A 2 : 8.76±0.22) and Ro 04‐6790 ( p A 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.British Journal of Pharmacology (2006) 148 , 1133–1143. doi: 10.1038/sj.bjp.0706827