PT  - JOURNAL ARTICLE
AU  - P A Maguire
AU  - J J Perez
AU  - N F Tsai
AU  - L Rodriguez
AU  - M F Beatty
AU  - H O Villar
AU  - J J Kamal
AU  - C Upton
AU  - A F Casy
AU  - G H Loew
TI  - Molecular mechanism of delta-selectivity of indole analogs of nonpeptide opioids.
DP  - 1993 Dec 01
TA  - Molecular Pharmacology
PG  - 1246--1251
VI  - 44
IP  - 6
4099  - http://molpharm.aspetjournals.org/content/44/6/1246.short
4100  - http://molpharm.aspetjournals.org/content/44/6/1246.full
SO  - Mol Pharmacol1993 Dec 01; 44
AB  - A combined experimental and computational approach was used to understand the mechanism of delta-receptor selectivity of a series of nonpeptide opioids. Six pairs of fused ring opioids/indole derivatives were studied. Receptor-binding assays using [3H][D-Ala2-MePhe4-Gly-ol]-enkephalin (mu), [3H][D-Pen2-D-Pen5]-enkephalin (delta), and [3H]U-69593 (kappa) were performed in guinea pig whole-brain membranes. Agonist activity was determined in norbinaltorphimine- or beta-funaltrexamine-treated guinea pig ileum (mu and kappa) and beta-funaltrexamine-treated mouse vas deferens (delta). Steric and electronic properties were calculated for each compound. Although the parent compounds were selective 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 delta-recognition is likely interaction with a lipophilic site in the receptor. 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.