Musings on α4β2 nicotinic acetylcholine (nACh) receptor pharmacophore models

Several pharmacophore models were previously formulated to account for the actions of nicotinic acetylcholinergic (nACh) agents. Most of these models were developed without express consideration of specific radioligand binding data because such data were not available at the time the models were described. In this review, the ability of these models to account for the binding of nicotinic agents at alpha4beta2 nACh receptors (or rat brain receptors for which alpha4beta2 receptors are the major component) is assessed. It seems that none of the early models can adequately explain the binding of these agents as a group. Furthermore, different series of nicotinic agents behave differently depending upon the nature of terminal amine substituents and the spacer that separates the amine from the pyridine ring. A region of bulk tolerance has been identified that accommodates substituents on some nicotinic ligands, but not the same substituents at seemingly corresponding locations of others. The concept of multiple modes of binding has been previously raised and, clearly, cannot yet be discarded. Nevertheless, new vector models seemingly provide a better picture of nACh receptor binding and account for many of the shortcomings associated with the earlier models.