Design, synthesis, and biological evaluation of pirenzepine analogs bearing a 1,2-cyclohexanediamine and perhydroquinoxaline units in exchange for the piperazine ring as antimuscarinics

Pirenzepine (2) is one of the most selective muscarinic M1 versus M2 receptor antagonists known. A series of 2 analogs, in which the piperazyl moiety was replaced by a cis- and trans-cyclohexane-1,2-diamine (3–6) or a trans- and cis-perhydroquinoxaline rings (7 and 8) were prepared, with the aim to investigate the role of the piperazine ring of 2 in the interaction with the muscarinic receptors. The structural change leading to compounds 3–6 abolished in binding assays the muscarinic M1/M2 selectivity of 2, due to an increased M2 affinity. Rather, compounds 3–6 displayed a reversed selectivity showing more affinity at the muscarinic M2 receptor than at all the other subtypes tested.