title: Dihydrocodeinone-hydrazone, dihydrocodeinone-oxime, naloxone-3-OMe-oxime, and clocinnamox fail to irreversibly inhibit opioid kappa receptor binding.
abstract: Previous work from our lab identified two subtypes of the opioid kappa receptor. Whereas the kappa1 receptor can be labeled by [3H]U69,593 (5 alpha,7 alpha,8 beta-(-)- N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro(4,5)dec-8-yl]-phenyl- benzeneacetamide), the kappa2 receptor can be labeled by [125I]OXY (6 beta-125iodo-3,14-dihydroxy-17-cyclopropylmethyl-4,5 alpha-epoxymorphinan). Other data demonstrate that [125I]IOXY, like [3H]bremazocine, labels two populations of kappa2 receptors in guinea pig brain: kappa2a and kappa2b binding sites. In the present study, we tested the hypothesis that certain dihydrocodeinone and oxicodone derivatives, which have been shown to irreversibly block low affinity [3H]naloxone binding sites, would also bind irreversibly to opioid kappa receptor subtypes. We also tested the novel irreversible mu receptor antagonist, clocinnamox (14 beta-(p-chlorocinnamoylamino)-7,8-dihydro-N-cyclopropylmethylno rmorphinone mesylate). Wash-resistant inhibition (WRI) assays were conducted to detect apparent irreversible inhibition. The proportion of WRI attributable to inhibition of receptor binding, termed receptor inhibition (RI), was calculated by the equation: RI = WRI (wash-resistant inhibition) - SI (supernatant inhibition or inhibition attributable to residual drug.) Dihydrocodeinone-hydrazone, dihydrocodeinone-oxime and naloxone-3-OMe-oxime failed to produce any wash-resistant inhibition of kappa receptor binding. In contrast, preincubating guinea pig membranes with 1 microM clocinnamox produced a substantial degree of wash-resistant inhibition (greater than 90%) at kappa1 and kappa2 binding sites. However, as indicated by supernatant inhibition values of 70% to 90%, there was a large amount of residual clocinnamox which remained despite the use of an extensive washing procedure.(ABSTRACT TRUNCATED AT 250 WORDS)
authors: Clinical Psychopharmacology Section, NIDA/NIH Addiction Research Center, Baltimore, Maryland 21224.
authors: Q
authors: Q
authors: Ni
authors: H
authors: H
authors: Xu
authors: J S
authors: JS
authors: Partilla
authors: B R
authors: BR
authors: de Costa
authors: K C
authors: KC
authors: Rice
authors: A
authors: A
authors: Borsodi
authors: S
authors: S
authors: Hosztafi
authors: R B
authors: RB
authors: Rothman
mesh_terms: D000818:Animals; D002934:Cinnamates / Q000494:pharmacology; D006168:Guinea Pigs; D006853:Hydrocodone / Q000031:analogs & derivatives / Q000494:pharmacology; D009022:Morphine Derivatives / Q000494:pharmacology; D009270:Naloxone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology*; D011869:Radioligand Assay; D017473:Receptors, Opioid, kappa / Q000378:metabolism*
chemical_list: D002934:Cinnamates; D009022:Morphine Derivatives; D009292:Narcotic Antagonists; D017473:Receptors, Opioid, kappa; C091497:dihydrocodeinone hydrazone; C091496:dihydrocodeinone oxime; C091498:naloxone-3-O-methyl-oxime; C076806:clocinnamox; D009270:Naloxone; D006853:Hydrocodone