MOLECULAR MECHANISM OF DELTA-SELECTIVITY OF INDOLE ANALOGS OF NONPEPTIDE OPIOIDS

A combined experimental and computational approach was used to underst and the mechanism of delta-receptor selectivity of a series of nonpept ide opioids. Six pairs of fused ring opioids/indole derivatives were s tudied. Receptor-binding assays using [H-3][D-Ala2-MePhe 4-Gly-ol]-enk ephalin (mu), [H-3][D-Pen2-D-Pen5]-enkephalin (delta), and [H-3]U-6959 3 (kappa) were performed in guinea pig whole-brain membranes. Agonist activity was determined in norbinal-torphimine- or beta-funaltrexamine -treated guinea pig ileum (mu and kappa) and beta-funaltrexamine-treat ed mouse vas deferens (delta). Steric and electronic properties were c alculated for each compound. Although the parent compounds were select ive for the mu-receptor, the indole analogs displayed selectivity for the delta-site because of a decrease in mu-affinity accompanied by an increase in delta-affinity. The indole analogs displayed little or no activity at the delta-receptor. The role of the indole in enhanced del ta-recognition is likely interaction with a lipophilic site in the rec eptor. The diminished mu-affinity of the indole analogs is a result of the loss of the carbonyl oxygen as the proton-accepting center, which we have previously determined to be important for recognition of the mu-receptor.