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Pharmacological profile of a potent, efficacious fentanyl derivative in rhesus monkeys (1992)

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.. Peer Reviewed. http://deepblue.lib.umich.edu/bitstream/2027.42/46340/1/213_2005_Article_BF02245876.pdf

Publication details

Download	, http://hdl.handle.net/2027.42/46340 http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=retrieve&db=pubmed&list_uids=1365629&dopt=citation
Publisher	Springer-Verlag
Contributors	Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA, Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA; Department of Psychology, University of Michigan, Ann Arbor, MI, USA, Department of Pharmacology and Experimental Therapeutics, Louisiana State University, Medical Center, 1100 Florida Avenue, 70119, New Orleans, LA, USA, Laboratory of Medicinal Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA, Laboratory of Medicinal Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA, Ann Arbor
Repository	University of Michigan (United States)
Keywords	Biomedicine, Self administration, Drug discrimination, Competitive antagonism, Fentanyl, Psychiatry, Respiratory function, Pharmacology/Toxicology, Opioid, Analgesia, Rhesus monkey, Psychiatry, Neurosciences, Chemistry, Biological Chemistry, Science, Health Sciences
Type	Original Investigations
Language	English