Abstract
The recent synthesis of fentanyl derivatives, some of which appear to have novel profiles of pharmacological effects, has provided compelling evidence that μ opioid efficacy might be altered systematically by modifications in the parent compound fentanyl. In the present study a new 4-(heteroanilido)-piperidine, compound 28, was studied for its effects in rhesus monkeys. In self-administration studies compound 28 maintained rates of lever pressing similar to those maintained by alfentanil; the reinforcing effects of compound 28 were attenuated by the opioid antagonist quadazocine. In drug discrimination studies compound 28 did not substitute for the κ agonist ethylketocyclazocine and did substitute for the μ agonist alfentanil. In morphine-treated subjects discriminating between saline and naltrexone, compound 28 did not substitute for naltrexone; however, in morphine-abstinent subjects compound 28 reversed naltrexone lever responding. Moreover, this discriminative stimulus effect in morphine-abstinent subjects was antagonized by naltrexone and by quadazocine in a manner consistent with μ receptor mediation. Compound 28 also was an effective analgesic in a warm-water, tail-withdrawal procedure and it decreased markedly respiratory function. The analgesic effects as well as the respiratory depressant effects of compound 28 were antagonized by quadazocine. Together, these results show compound 28 to be a potent, efficacious μ agonist of similar potency to alfentanil. Large differences in apparent efficacy at μ receptors between compound 28 and another compound in this series (mirfentanil), clearly demonstrate that, within this chemical family, small chemical changes can confer significant differences in pharmacologic effect.
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References
Aceto MD, Bowman ER, Harris LS, May EL (1990) Dependence studies of new compounds in the rhesus monkey and mouse. In: Harris L (ed) Proceedings of the Committee on Problems of Drug Dependence, National Institute on Drug Abuse Research Monograph # 105, US Government Printing Office, Washington, DC, pp 640–681
Arunlakshana O, Schild HO (1959) Some quantitative uses of drug antagonists. Br J Pharmacol 14:48–58
Bagley JR, Wynn RL, Rudo FG, Doorley BM, Spencer HK, Spaulding T (1989) New 4-(heteroanilido)piperidines, structurally related to the pure opioid agonist fentanyl, with agonist and/or antagonist properties. J Med Chem 32:663–671
Bertalmio AJ, Woods JH (1987) Differentiation between μ and κ receptor-mediated effects in opioid drug discrimination: Apparent pA2 analysis. J Pharmacol Exp Ther 243:591–597
Bertalmio AJ, Woods JH (1989) Reinforcing effect of alfentanil is mediated by μ opioid receptors: apparent pA2 analysis. J Pharmacol Exp Ther 251:455–460
Dykstra LA, Woods JH (1986) A tail withdrawal procedure for assessing analgesic activity in rhesus monkeys. J Pharmacol Methods 15:263–269
Dykstra LA, Gmerek DE, Winger G, Woods JH (1987) Kappa opioids in rhesus monkeys. II. Analysis of the antagonistic actions of quadazocine andβ-funaltrexamine. J Pharmacol Exp Ther 242:421–427.
France CP, de Costa BR, Jacobson AE, Rice KC, Woods JH (1990a) Apparent affinity of opioid antagonists in morphine-treated rhesus monkeys discriminating between saline and naltrexone. J Pharmacol Exp Ther 252:600–604
France CP, Winger G, Medzihradsky F, Smith CB, Woods JH, Seggel M, Rice K (1990b) In vitro and in vivo characterization of a fentanyl-related compound with opioid agonist and antagonist effects. In: van Ree JM, Mulder AH, Wiegant VM, van Wimersma Greidanus TB (eds) New leads in opioid research. Excerpta Medica, Amsterdam, pp 71–72
France CP, Winger G, Medzihradsky F, Seggel MR, Rice KC, Woods JH (1991) Mirfentanil: pharmacological profile of a novel fentanyl derivative with opioid and nonopioid effects. J Pharmacol Exp Ther 258:502–510
France CP, Winger G, Seggel MR, Rice KC, Woods JH (1992) In vivo pharmacology of potent, μ-selective opioids: variations in opioid efficacy. In: Harris L (ed) Proceedings of the Committee on Problems of Drug Dependence, National Institute on Drug Abuse Research Monograph #119, US Government Printing Office, Washington, DC, p. 257
Howell LL, Bergman J, Morse WH (1988) Effects of levorphanol and several κ-selective opioids on respiration and behavior in rhesus monkeys. J Pharmacol Exp Ther 245:364–372
Ossipov MH, Bagley JR, Harris S, Lysko G, Messineo E, Bright D, D'Alonzo A, Spaulding TC (1990) A-3508: a potent opioid agonist with minimal respiratory depression. Pain 5:S195
Takemori AE (1974) Determination of pharmacological constants: use of narcotic antagonists to characterize analgesic receptors. In: Braude MC, Harris LS, May EL, Smith JP, Villarreal JE (eds) Narcotic antagonists. Advances in biochemical psychopharmacology, vol 8. Raven Press, New York, pp 335–344
Tallarida RJ, Cowan A, Adler MW (1979) pA2 and receptor differentiation: a statistical analysis of competitive antagonism. Life Sci 25:637–654
Winger G, Palmer RK, Woods JH (1989) Drug-reinforced responding: rapid determination of dose-response functions. Drug Alcohol Depend 24:135–142
Woods JH (1980) Narcotic-reinforced responding: a rapid evaluation procedure. Drug Alcohol Depend 5:223–230
Woods JH, Medzihradsky F, Smith CB, Winger GD, France CP (1990) Evaluation of new compounds for opioid activity. In: Harris L (ed) Proceedings of the Committee on Problems of Drug Dependence, National Institute on Drug Abuse Research Monograph #105, US Government Printing Office, Washington, DC, pp 682–724
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Supported by USPHS Grants DA 05018 and DA 00254. Portions of these results were presented at the 53rd Annual Scientific Meeting of the Committee on Problems of Drug Dependence, Palm Beach (France et al. 1992). Animals used in these studies were maintained in accordance with the University Committee on the Use and Care of Animals, Louisiana State University Medical Center and University of Michigan, and guidelines of the Committee on the Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources, National Research Council (Department of Health, Education and Welfare, Publication No. (NIH) 85-23, revised 1983).
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France, C.P., Winger, G., Seggel, M.R. et al. Pharmacological profile of a potent, efficacious fentanyl derivative in rhesus monkeys. Psychopharmacology 109, 291–298 (1992). https://doi.org/10.1007/BF02245876
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DOI: https://doi.org/10.1007/BF02245876