Quantitative structure–selectivity relationship for M2 selectivity between M1 and M2 of piperidinyl piperidine derivatives as muscarinic antagonists

Abstract

Muscarinic M2 receptor antagonists with high subtype selectivity (M2/M1) will decrease the toxicity in central nervous system in treatment of AD. The exploration of quantitative structure–selectivity relationship (QSSR) to muscarinic M2 receptor antagonists will provide design information for drug with fewer side effects. In this paper, CoMFA models of p K i(M1), p K i(M2) and p[ K i(M2)/ K i(M1)] (p K i(M2) − p K i(M1)) were used to study the subtype selectivity (M2/M1) of piperidinyl piperidine derivatives as muscarinic M2 subtype receptor antagonists. The parameters of the three models are: 0.633, 0.636 and 0.726 for cross-validated r 2 ( r cv 2 ), 0.109, 0.204 and 0.09 for the Standard error of estimate (SD), respectively. The results show the model of p[ K i(M2)/ K i(M1)] is the best one for design of piperidinyl piperidine derivatives as muscarinic antagonists with high subtype selectivity (M2/M1).