title: Probing the opioid receptor complex with (+)-trans-SUPERFIT. II. Evidence that mu ligands are noncompetitive inhibitors of the delta cx opioid peptide binding site.
abstract: Previous studies delineated two classes of delta binding sites; a delta binding site not associated with the opioid receptor complex, termed the delta ncx site, and a delta site associated with the opioid receptor complex, termed the delta cx site. The delta ncx site has high affinity for [D-Pen2,D-Pen5]enkephalin, and is synonymous with what is now identified as the delta 1 binding site. Pretreatment of membranes with the delta-selective acylating agents FIT, or (+)-trans-SUPERFIT, deplete membranes of the delta ncx binding site, which permits the selective labeling of the delta cx binding site with [3H][D-Ala2,Leu5]enkephalin. The present study compared the properties of the delta cx binding site present in brain membranes pretreated with (+)-trans-SUPERFIT with the properties of the delta cx site present in untreated membranes. The major findings are: 1) pretreatment of membranes with (+)-trans-SUPERFIT decreased the IC50 values of delta-preferring drugs, and increased the IC50 values of mu-preferring drugs, for the delta cx binding site; 2) the degree of delta selectivity was highly correlated with the magnitude of the (+)-trans-SUPERFIT-induced shift in the IC50 values; 3) the ligand-selectivity patterns of the mu and delta cx sites present in (+)-trans-SUPERFIT-pretreated membranes were poorly correlated; 4) whereas mu-preferring drugs were noncompetitive inhibitors of [3H][D-Ala2,Leu5]enkephalin binding to the delta cx site, delta-preferring drugs were competitive inhibitors.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Clinical Psychopharmacology Section, NIDA Addiction Research Center, Baltimore, MD 21224.
authors.forename: R B
authors.initials: RB
authors.lastname: Rothman
authors.forename: A
authors.initials: A
authors.lastname: Mahboubi
authors.forename: V
authors.initials: V
authors.lastname: Bykov
authors.forename: C H
authors.initials: CH
authors.lastname: Kim
authors.forename: B R
authors.initials: BR
authors.lastname: de Costa
authors.forename: A E
authors.initials: AE
authors.lastname: Jacobson
authors.forename: K C
authors.initials: KC
authors.lastname: Rice
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D005283:Fentanyl / Q000031:analogs & derivatives*; D051381:Rats; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors*; D017450:Receptors, Opioid, mu / Q000378:metabolism*
chemical_list: D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; C046222:3-methylfentanyl isothiocyanate; D005283:Fentanyl