Structure-activity relationships for drugs binding to the agonist and antagonist states of the primary morphine receptor.

Thirty-three opiate drugs have been considered in an investigation of the geometric and electronic features required for association with the agonist and antagonist states of the principal morphine receptor. Conformational analysis was carried out by means of molecular mechanics, and electronic properties were calculated with an ab initio SCF-MO procedure using FSGO basis sets. Statistical analysis of receptor binding based on a free-energy model reveals several properties of the molecules under study that affect the stability of the drug-receptor complex. The results suggest that the same drug conformation is involved in binding at both the agonist and antagonist states of the receptor. A single set of drug features serves to rationalize association with both receptor states, but differences in binding-site topography are revealed by the relative importance of the various structural features in the regression equations for the two states.