title: Opioid activity of spinally selective analogues of N-naphthoyl-β-naltrexamine in HEK-293 cells and mice.
abstract: Using the selective mu-kappa agonist, N-naphthoyl-β-naltrexamine 1, as the prototype ligand, a series of closely related naphthalene analogues were synthesized to study the chemical space around the naphthalene moiety in an effort to evaluate how receptor selectivity is affected by chemical modification. Nine analogues (2-10) of compound 1 were synthesized and tested on HEK-293 cells expressing homomeric and heteromeric opioid receptors, and in the mouse tail-flick assay. It was found that a small change in structure produces profound changes in selectivity in this series. This is exemplified by the discovery that introduction of a 6-fluoro group transforms 1 from a selective mu-kappa heteromeric receptor agonist to a delta-preferring agonist 7. The in vivo studies reveal that many of the ligands are more potent spinally than supraspinally and devoid of tolerance.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455, United States.
authors.forename: Morgan
authors.initials: M
authors.lastname: Le Naour
authors.forename: Mary M
authors.initials: MM
authors.lastname: Lunzer
authors.forename: Mike D
authors.initials: MD
authors.lastname: Powers
authors.forename: Philip S
authors.initials: PS
authors.lastname: Portoghese
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D054333:Drug Partial Agonism; D004361:Drug Tolerance; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007278:Injections, Spinal; D008024:Ligands; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D055503:Protein Multimerization; D017465:Receptors, Opioid, delta / Q000819:agonists*; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000235:genetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D008024:Ligands; C571180:N-naphthoyl-beta-naltrexamine; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D009271:Naltrexone; D002118:Calcium