STRUCTURAL FEATURES IMPORTANT FOR SIGMA(1) RECEPTOR-BINDING

Two problems that have hampered a receptor research are (i) a lack of high-affinity agents and iii) the recent identification Of multiple populations of a receptors (i.e., sigma(1) and sigma(2) sites). Recently, several high-affinity sigma ligands have been identified, and the term superpotent sigma ligands has been coined to describe agents with K-i values of <1 nM. We have previously shown that appropriately N-substituted phenylalkylamines bind at a receptors with high affinity. In the present investigation, we examine the structure-affinity relationships of these phenylalkylamine derivatives for sigma binding and describe some of the first superpotent sigma(1) ligands. A binding model was developed to account for the structural features of the phenylalkylamines that appear to be important for the interaction of these agents with sigma(1) sites.