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

Mol Pharmacol. 1993 Dec;44(6):1246-51.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Benzeneacetamides*
  • Binding Sites
  • Brain / drug effects
  • Brain / metabolism
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • Enkephalin, D-Penicillamine (2,5)-
  • Enkephalins / metabolism
  • Enkephalins / pharmacology
  • Guinea Pigs
  • In Vitro Techniques
  • Indoles / metabolism
  • Indoles / pharmacology*
  • Molecular Sequence Data
  • Pyrrolidines / metabolism
  • Pyrrolidines / pharmacology
  • Receptors, Opioid, delta / drug effects*
  • Receptors, Opioid, delta / metabolism
  • Receptors, Opioid, kappa / drug effects
  • Receptors, Opioid, kappa / metabolism
  • Receptors, Opioid, mu / drug effects
  • Receptors, Opioid, mu / metabolism

Substances

  • Benzeneacetamides
  • Enkephalins
  • Indoles
  • Pyrrolidines
  • Receptors, Opioid, delta
  • Receptors, Opioid, kappa
  • Receptors, Opioid, mu
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • Enkephalin, D-Penicillamine (2,5)-
  • U 69593