Structure-activity relationships in 2,2-diphenyl-2-ethylthioacetic acid esters: Unexpected agonistic activity in a series of muscarinic antagonists

As a continuation of previous research on anticholinergic drugs derived fro m 2,2-diphenyl-2-ethylthioacetic acid, several 5,5-diphenyl-5-ethylthio-2-p entynamines (2-11) were synthetised and their antimuscarinic activity on M1 -4 receptor subtypes was evaluated by functional tests and binding experime nts. One of the compounds obtained showed unexpected agonistic activity in functional experiments on M-2 receptors. Since the compound carried a pheny lpiperazine moiety, other similar compounds (12-17) were prepared and found to be endowed with similar behaviour. These ligands, although possessing t he bulky structure characterising muscarinic antagonists, display agonistic activity at M-2 subtypes while, as expected, behaving as antagonists on M- 3 and Mg subtypes. On M-1 subtypes, they show agonistic activity which, how ever, is not blocked by atropine. The peculiar pharmacological profile of t hese compounds is of interest for studying muscarinic receptor subtypes. (C ) 2001 Elsevier Science Ltd. All rights reserved.