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Molecular mechanism of delta-selectivity of indole analogs of nonpeptide opioids

PA Maguire, JJ Perez, NF Tsai, L Rodriguez, MF Beatty, HO Villar, JJ Kamal, C Upton, AF Casy and GH Loew

Molecular Research Institute, Palo Alto, California 94304.

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.

Volume 44, Issue 6, pp. 1246-1251, 12/01/1993
Copyright © 1993 by American Society for Pharmacology and Experimental Therapeutics




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Copyright © 1993 by the American Society for Pharmacology and Experimental Therapeutics