Pharmacodynamic and pharmacokinetic actions of ketocyclazocine enantiomers in the dog: absence of sigma- or phencyclidine-like activity

DB Vaupel and EJ Cone

Neuropharmacology Laboratory, National Institute on Drug Abuse, Baltimore, Maryland.

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.

Volume 256, Issue 1, pp. 211-221, 01/01/1991
Copyright © 1991 by American Society for Pharmacology and Experimental Therapeutics

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