title: Kappa opiate receptor multiplicity: evidence for two U50,488-sensitive kappa 1 subtypes and a novel kappa 3 subtype.
abstract: Kappa receptor multiplicity is a complex area. We now present evidence from binding studies suggesting the existence of four kappa receptor subtypes. The guinea pig cerebellum contains high levels of U50,488-sensitive, or kappa 1, receptors. Kappa opiates (U50,488, tifluadom, Mr2034, Mr2266 and Win44,441) compete [3H]ethylketocyclazocine binding to kappa 1 receptors with kappa, values under 10 nM and Hill coefficients of approximately one, as does dynorphin A (kappa 1, 0.27 +/- 0.05 nM; Hill coefficient, 0.83 +/- 0.20, n = 4). However, competition studies with dynorphin B yield a Hill coefficient of 0.46 +/- 0.03 (n = 5) and nonlinear regression analysis of the competition curve is best fit by two sites. alpha-Neoendorphin Neoendorphin competition curves (Hill coefficient, 0.46 +/- 0.07; n = 3) also were best fit with two components. Competition studies with both alpha-neoendorphin and dynorphin B together suggest that both compounds label the same site with high affinity. Similar results were obtained using [3H]U69,593. Dynorphin B and alpha-neoendorphin competed binding with Hill coefficients of 0.45 +/- 0.04 (n = 3) and 0.59 +/- 0.09 (n = 3), respectively. These data suggest two subtypes of kappa 1 receptors in the guinea pig cerebellum: kappa 1a and kappa 1b. Classical kappa opiates and dynorphin A have high affinity for both subtypes whereas dynorphin B and alpha-neoendorphin label kappa 1b over 50-fold more potently than kappa 1a sites. [3H]Naloxone benzoylhydrazone [( 3H]NalBzoH) labels a novel, U50,488-insensitive kappa receptor subtype, kappa 3, in membranes from calf striatum, rat and mouse brain. We now have developed a relatively selective assay in calf striatum.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Cotzias Laboratory of Neuro-Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: J A
authors.initials: JA
authors.lastname: Clark
authors.forename: L
authors.initials: L
authors.lastname: Liu
authors.forename: M
authors.initials: M
authors.lastname: Price
authors.forename: B
authors.initials: B
authors.lastname: Hersh
authors.forename: M
authors.initials: M
authors.lastname: Edelson
authors.forename: G W
authors.initials: GW
authors.lastname: Pasternak
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000818:Animals; D001665:Binding Sites; D002417:Cattle; D002531:Cerebellum / Q000032:analysis; D003496:Cyclazocine / Q000031:analogs & derivatives / Q000378:metabolism; D004492:Edetic Acid / Q000494:pharmacology; D016314:Ethylketocyclazocine; D006168:Guinea Pigs; D066298:In Vitro Techniques; D009270:Naloxone / Q000031:analogs & derivatives / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology*; D011957:Receptors, Opioid / Q000032:analysis* / Q000378:metabolism; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu
chemical_list: D011759:Pyrrolidines; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; C058380:naloxone benzoylhydrazone; D009270:Naloxone; D016314:Ethylketocyclazocine; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D004492:Edetic Acid; D003496:Cyclazocine