title: Pharmacological activities of optically pure enantiomers of the kappa opioid agonist, U50,488, and its cis diastereomer: evidence for three kappa receptor subtypes.
abstract: De Costa et al. (FEBS Lett. 223, 335; 1987) recently described the synthesis of optically pure enantiomers of (+/-)-trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl] benzeneacetamide (U50,488). In the present study we examined the in vitro opioid receptor selectivity of (-)-(1S,2S)-U50,488, (+)-(1R,2R)-U50,488 and (+/-)-cis-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl] benzeneacetamide (the cis diasteromers of U50,488), as well as their pharmacological activities in rhesus monkeys. Using [3H]5 alpha,7 alpha,8 beta-(-)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro (4,5)dec-8-yl]-phenyl-benzeneacetamide ([3H]U69,593) to label kappa binding sites of guinea pig membranes, the apparent dissociation constants of the enantiomers of U50,488 were 0.89 and 299 nM, for the (S,S) and (R,R) enantiomers, respectively. The (-)-cis and (+)-cis diastereomers had apparent Kds of 167 and 2715 nM, respectively. Binding surface analysis of the interaction of (-)-(1S,2S)-U50,488 with kappa binding sites labeled by [3H]bremazocine resolved two binding sites at which (-)-(1S,2S)-U50,488 had Kds of 30 and 10,485 nM, respectively. The (+/-)-cis, (-)-cis and (+)-cis diastereomers of U50,488 (1 microM) did not inhibit [3H]bremazocine binding. Rhesus monkeys were trained to discriminate ethylketocyclazocine (EKC) and saline. All compounds tested substituted completely for EKC. The order of potency was (-)-(1S,2S)-U50,488 greater than (+/-)-U50,488 greater than (+/-)-cis diastereomer of U50,488 greater than (+)-(1R,2R)-U50,488.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Unit on Receptor Studies, LCS, NIMH, Bethesda, MD 20892.
authors.forename: R B
authors.initials: RB
authors.lastname: Rothman
authors.forename: C P
authors.initials: CP
authors.lastname: France
authors.forename: V
authors.initials: V
authors.lastname: Bykov
authors.forename: B R
authors.initials: BR
authors.lastname: De Costa
authors.forename: A E
authors.initials: AE
authors.lastname: Jacobson
authors.forename: J H
authors.initials: JH
authors.lastname: Woods
authors.forename: K C
authors.initials: KC
authors.lastname: Rice
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D044482:Benzeneacetamides; D001569:Benzodiazepines / Q000494:pharmacology; D001575:Benzomorphans / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D003496:Cyclazocine / Q000031:analogs & derivatives / Q000494:pharmacology; D004192:Discrimination, Psychological / Q000187:drug effects; D016314:Ethylketocyclazocine; D005260:Female; D006168:Guinea Pigs; D008253:Macaca mulatta; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D011957:Receptors, Opioid / Q000378:metabolism*; D017473:Receptors, Opioid, kappa; D013237:Stereoisomerism
chemical_list: D000700:Analgesics; D044482:Benzeneacetamides; D001575:Benzomorphans; D011759:Pyrrolidines; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D001569:Benzodiazepines; D016314:Ethylketocyclazocine; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; C027248:bremazocine; C045444:U 69593; D003496:Cyclazocine; C035470:tifluadom