Electronic and conformational features of a series of N-protonated benzomorphan molecules: N-substituent effects on relative binding at the agonist and antagonist states of the opioid receptor

Abstract

The fsgo molecular fragment technique has been used to perform ab initio scf-mo calculations on a series of N-protonated benzomorphan congeners. Characteristics of high-energy occupied and low-energy unoccupied molecular orbitals (homos and lumos) are discussed in this report together with correlations between orbitals from different molecules. An investigation of the N-substituent conformation has been carried out for each molecule by means of an empirical molecular mechanics procedure. Based upon geometric and electronic comparisons, a model has been developed to rationalize the relative affinities of the drugs for the agonist and antagonist states of the morphine receptor. Two features of the N-substituents are considered to govern the antagonist/agonist ratio: (1) the availability of a suitable localized lumo to serve as an electron acceptor in charge-transfer interactions, and (2) a steric factor represented by a cis configuration in the moiety N—CH2—CC—CH3.