Theoretical quantitative structure-activity analysis of quinuclidine-based muscarinic cholinergic receptor ligands

Quantitative structure-activity relationship analysis using ad hoc theoretical molecular descriptors was performed on a set of 22 quinuclidine-based muscarinic cholinergic receptor ligands. The results obtained support quantitatively a pharmacophoric interacting model which suggests that once the essential H-bonding interaction between the protonated quinuclidine nitrogen atom and a protophilic counterpart in the receptor is satisfied, different mechanisms of interaction become operative in order to differentiate between agonists, partial agonists and antagonists. In fact, the agonist behaviour is characterized by two H-bonding interactions, whereas mainly lipophilic interactions characterize the antagonistic behaviour. Finally, both the H-bond acceptor propensity of the agonists and lipophilic features of the antagonists are better accounted for by theoretical descriptors computed on the pharmacologically active protonated forms than by those computed on the neutral forms.