title: Molecular mechanism of delta-selectivity of indole analogs of nonpeptide opioids.
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.
authors.affiliation: Molecular Research Institute, Palo Alto, California 94304.
authors.forename: P A
authors.initials: PA
authors.lastname: Maguire
authors.forename: J J
authors.initials: JJ
authors.lastname: Perez
authors.forename: N F
authors.initials: NF
authors.lastname: Tsai
authors.forename: L
authors.initials: L
authors.lastname: Rodriguez
authors.forename: M F
authors.initials: MF
authors.lastname: Beatty
authors.forename: H O
authors.initials: HO
authors.lastname: Villar
authors.forename: J J
authors.initials: JJ
authors.lastname: Kamal
authors.forename: C
authors.initials: C
authors.lastname: Upton
authors.forename: A F
authors.initials: AF
authors.lastname: Casy
authors.forename: G H
authors.initials: GH
authors.lastname: Loew
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D044482:Benzeneacetamides; D001665:Binding Sites; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000378:metabolism / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology*; D008969:Molecular Sequence Data; D011759:Pyrrolidines / Q000378:metabolism / Q000494:pharmacology; D017465:Receptors, Opioid, delta / Q000187:drug effects* / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000187:drug effects / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000378:metabolism
chemical_list: D044482:Benzeneacetamides; D004745:Enkephalins; D007211:Indoles; D011759:Pyrrolidines; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D020881:Enkephalin, D-Penicillamine (2,5)-; C045444:U 69593