title: Interaction of beta-funaltrexamine with [3H]cycloFOXY binding in rat brain: further evidence that beta-FNA alkylates the opioid receptor complex.
abstract: beta-Funaltrexamine (beta-FNA) is an alkylating derivative of naltrexone. In addition to acting as an irreversible inhibitor of mu-receptor-mediated physiological effects, intracerebroventricular (i.c.v.) administration of beta-FNA to rat attenuates the ability of selective delta receptor antagonists and naloxone to reverse delta receptor-mediated effects. Moreover, recent work demonstrated that i.c.v. administration of beta-FNA alters the conformation of the opioid receptor complex, as inferred by a decrease in the Bmax of the lower affinity [3H][D-ala2,D-leu5]enkephalin binding site. Consistent with the decreased potency of naloxone as an inhibitor of delta receptor mediated effects, beta-FNA doubled the naloxone IC50 for displacing [3H][D-ala2,D-leu5]enkephalin from its lower affinity binding site. These data collectively support the hypothesis that the opioid receptor complex postulated to mediate mu-delta interactions in vivo is identical to the opioid receptor complex as defined by vitro ligand binding studies. A direct prediction of this hypothesis is that beta-FNA should increase the Kd of antagonists for the mu binding site (mu cx) of the receptor complex. The data reported in this paper demonstrate that beta-FNA doubled the IC50 of the potent narcotic antagonist, 6-desoxy-6 beta-fluoronaltrexone (cycloFOXY) for displacing [3H][D-ala2,D-leu5]enkephalin from its lower affinity binding site, and doubled the Kd of [3H]cycloFOXY for its mu binding site, providing additional data that the mu binding site labeled by [3H]cycloFOXY is the mu binding site of the opioid receptor complex. beta-FNA also altered the kappa binding site labeled by [3H]cycloFOXY, and when administered intrathecally to mice, beta-FNA produced a longlasting antinociception in the acetic acid writhing test.
authors.affiliation: Unit on Receptor Studies, Laboratory of Medicinal Chemistry, NIDDK, Bethesda, Maryland 20892.
authors.forename: R B
authors.initials: RB
authors.lastname: Rothman
authors.forename: V
authors.initials: V
authors.lastname: Bykov
authors.forename: A
authors.initials: A
authors.lastname: Mahboubi
authors.forename: J B
authors.initials: JB
authors.lastname: Long
authors.forename: Q
authors.initials: Q
authors.lastname: Jiang
authors.forename: F
authors.initials: F
authors.lastname: Porreca
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
authors.forename: J W
authors.initials: JW
authors.lastname: Holaday
mesh_terms: D000477:Alkylating Agents / Q000494:pharmacology*; D000478:Alkylation; D000700:Analgesics; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D016308:Enkephalin, Leucine-2-Alanine / Q000378:metabolism; D007276:Injections, Intraventricular; D007700:Kinetics; D008024:Ligands; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000187:drug effects / Q000378:metabolism*; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D013499:Surface Properties
chemical_list: D000477:Alkylating Agents; D000700:Analgesics; D008024:Ligands; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D009271:Naltrexone; D016308:Enkephalin, Leucine-2-Alanine; C066758:6-deoxy-6-fluoronaltrexone; C024524:beta-funaltrexamine