CHARACTERIZATION OF RO-04-6790 AND RO-63-0563 - POTENT AND SELECTIVE ANTAGONISTS AT HUMAN AND RAT 5-HT6 RECEPTORS

1 This study describes the in vitro characterization of two potent and selective 5-HT6 receptor antagonists at the rat and human recombinant 5-HT6 receptor.2 In binding assays with [H-3]-LSD, 4-amino-N-(2,6 bis -melhylamino-pyrimidin-4-yl)-benzene sulphonamide (Ro 04-6790) and 4-a mino-N-(2,6 bis-methylamino-pyridin-4-yl)-benzene sulphonamide (Ro 63- 0563) had mean pK(i) values +/-s.e.mean at the rat 5-HT6 receptor of 7 .35+/-0.04 and 7.83+/-0.01, respectively and pK(i) values at the human 5-HT6 receptor of 7.26+/-0.06 and 7.91+/-0.02, respectively. 3 Both c ompounds were found to be over 100 fold selective for the 5-HT6 recept or compared to 23 (Ro 04-6790) and 69 (Ro 63-0563) other receptor bind ing sites. 4 In functional studies, neither compound had any significa nt effect on basal levels of cyclicAMP accumulation in Hela cells stab ly expressing the human 5-HT6 receptor, suggesting that the compounds are neither agonists nor inverse agonists at the 5-HT6 receptor. Howev er, both Ro 04-6790 and Ro 63-0563 behaved as competitive antagonists with mean +/-s.e.mean pA(2) values of 6.75 +/- 0.07 and 7.10 +/- 0.09, respectively. 5 In rats habituated to observation cages, Ro 04-6790 p roduced a behavioural syndrome similar to that seen following treatmen t with antisense oligonucleotides designed to reduce the expression of 5-HT6 receptors. This behavioural syndrome consisted of stretching, y awning and chewing. 6 Ro 04-6790 and Ro 63-0563 represent valuable pha rmacological tools for the identification of 5-HT6 receptors in natura l tissues and the study of their physiological function.