title: Pharmacodynamic and pharmacokinetic actions of ketocyclazocine enantiomers in the dog: absence of sigma- or phencyclidine-like activity.
abstract: The effects of the optical isomers and the racemic form of ketocyclazocine (KC) were compared with morphine and U-50,488H in the chronic spinal dog. l-KC and dl-KC produced depression of nociceptive reflexes, miosis, relaxation of the nictitating membrane and sedation, whereas d-KC lacked pharmacological activity. Peak plasma levels and distribution phase half-lives for dl-, l- and d-KC were similar, indicating no major dispositional differences between the isomers of KC despite a trend for d-KC to have a longer elimination half-life, slower plasma clearance and a greater apparent volume of distribution than l-KC. Although a relatively low dose of naltrexone (0.01 mg/kg) was sufficient to shift morphine dose-effect curves to the right, this dose of naltrexone was not sufficient to shift the dose-effect curves of dl-KC to the right. A dose of 1 mg/kg of naltrexone was required, consistent with the view that the effects were mediated by kappa opioid receptors. The overall pharmacological profile of l-KC differed from that of the more selective kappa opioid agonist U-50,488H, which produced both stimulatory and sedative effects. Neither l-KC nor U-50,488H produced pharmacological profiles typical of the sigma agonist d-N-allylnormetazocine or phencyclidine. The data suggest that the pharmacological activity of KC resides in the l-enantiomer, that the effects are kappa opioid receptor-mediated and that the binding of d-KC to haloperidol-sensitive sigma receptors does not produce N-allylnormetazocine- or phencyclidine-like actions in the dog.
authors.affiliation: Neuropharmacology Laboratory, National Institute on Drug Abuse, Baltimore, Maryland.
authors.forename: D B
authors.initials: DB
authors.lastname: Vaupel
authors.forename: E J
authors.initials: EJ
authors.lastname: Cone
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; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D016314:Ethylketocyclazocine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D009020:Morphine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009271:Naltrexone / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D011957:Receptors, Opioid / Q000187:drug effects / Q000502:physiology; D017473:Receptors, Opioid, kappa; D017480:Receptors, sigma; D013237:Stereoisomerism; D013997:Time Factors
chemical_list: D000700:Analgesics; D011759:Pyrrolidines; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D017480:Receptors, sigma; D016314:Ethylketocyclazocine; D009271:Naltrexone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; C012395:ketazocine; D009020:Morphine