Is a nitrogen atom an important pharmacophoric element in sigma ligand binding?

A lingering question in sigma receptor ligand development is whether a nitrogen atom serves as an important pharmacophoric clement in binding affinity. To address this question, we have synthesized several phenylalkylpiperidines and phenylalkylpiperazines and demonstrated that removal of the N atom from a typical phenylalkylpiperidine led to little or no binding to sigma receptors. Tn addition, where two N atoms occur in a compound, such as with phenylalkylpiperazines, the N atom on the longer alkyl chain appears to be more important. Thus, based on this study, the N atom is an important pharmacophoric element in the binding of phenylalkyllpiperidines and phenylalkylpiperazines to sigma receptors. (C) 2000 Elsevier Science Ltd. All rights reserved.