title: Na+ modulation, inverse agonism, and anorectic potency of 4-phenylpiperidine opioid antagonists.
abstract: Differences in the anorectic activity of morphinan (e.g., naltrexone) and 3,4-dimethyl-4-(3-hydroxyphenyl)piperidine (4PP) opioid receptor antagonists have been described. In an attempt to explain these differences, the influence of Na(+) on opioid binding affinity and functional activity of 4PP antagonists was compared to other opioid antagonists. The binding affinities of neutral antagonists were unaffected by the addition of Na(+), whereas that for the peptide, inverse agonist N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH (ICI174864) was increased. Similarly, the binding affinities of the 4PP antagonist (3R,4R)-1-((S)-3-hydroxy-3-cyclohexylpropyl)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidine (LY255582) and other 4PP antagonists were increased in the presence of Na(+) with the greatest effects at the delta opioid receptor followed by the mu and kappa opioid receptors, respectively. Similar to ICI174864, 4PP antagonists were found to inhibit basal GTPgamma[(35)S] binding at the delta opioid receptor indicating inverse agonist activity. A correlation was observed between the binding affinities in the presence of Na(+), the inverse agonist potency, and the anorectic potency of 4PP antagonists. These data suggest that 4PP antagonists differ from morphinan antagonists in their inverse agonist activity and suggest a relationship between inverse agonism and anorectic activity.
authors.affiliation: Endocrine Research, Lilly Research Laboratories, Lilly Corporate Center DC0403, Indianapolis, IN 46285, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Emmerson
authors.forename: Jamie H
authors.initials: JH
authors.lastname: McKinzie
authors.forename: Peggy L
authors.initials: PL
authors.lastname: Surface
authors.forename: Todd M
authors.initials: TM
authors.lastname: Suter
authors.forename: Charles H
authors.initials: CH
authors.lastname: Mitch
authors.forename: Michael A
authors.initials: MA
authors.lastname: Statnick
mesh_terms: D000818:Animals; D001067:Appetite Depressants; D001667:Binding, Competitive / Q000187:drug effects; D016466:CHO Cells; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D003510:Cyclohexanes / Q000494:pharmacology; D004174:Diprenorphine / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D008024:Ligands; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D011924:Rats, Zucker; D011957:Receptors, Opioid / Q000819:agonists* / Q000378:metabolism; D017465:Receptors, Opioid, delta / Q000819:agonists; D012964:Sodium / Q000378:metabolism*
chemical_list: D001067:Appetite Depressants; D003510:Cyclohexanes; D008024:Ligands; D009292:Narcotic Antagonists; D010880:Piperidines; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C070736:LY 243670; D004174:Diprenorphine; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D009271:Naltrexone; C048151:4-phenylpiperidine; D012964:Sodium