title: Synthesis, modeling, and pharmacological evaluation of UMB 425, a mixed μ agonist/δ antagonist opioid analgesic with reduced tolerance liabilities.
abstract: Opioid narcotics are used for the treatment of moderate-to-severe pain and primarily exert their analgesic effects through μ receptors. Although traditional μ agonists can cause undesired side effects, including tolerance, addition of δ antagonists can attenuate said side effects. Herein, we report 4a,9-dihydroxy-7a-(hydroxymethyl)-3-methyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one (UMB 425) a 5,14-bridged morphinan-based orvinol precursor synthesized from thebaine. Although UMB 425 lacks δ-specific motifs, conformationally sampled pharmacophore models for μ and δ receptors predict it to have efficacy similar to morphine at μ receptors and similar to naltrexone at δ receptors, due to the compound sampling conformations in which the hydroxyl moiety interacts with the receptors similar to orvinols. As predicted, UMB 425 exhibits a mixed μ agonist/δ antagonist profile as determined in receptor binding and [(35)S]GTPγS functional assays in CHO cells. In vivo studies in mice show that UMB 425 displays potent antinociception in the hot plate and tail-flick assays. The antinociceptive effects of UMB 425 are blocked by naloxone, but not by the κ-selective antagonist norbinaltorphimine. During a 6-day tolerance paradigm, UMB 425 maintains significantly greater antinociception compared to morphine. These studies thus indicate that, even in the absence of δ-specific motifs fused to the C-ring, UMB 425 has mixed μ agonist/δ antagonist properties in vitro that translate to reduced tolerance liabilities in vivo.
authors.affiliation: Department of Basic Pharmaceutical Sciences, West Virginia University , Morgantown, West Virginia 26506, United States.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Healy
authors.forename: Padmavani
authors.initials: P
authors.lastname: Bezawada
authors.forename: Jihyun
authors.initials: J
authors.lastname: Shim
authors.forename: Jace W
authors.initials: JW
authors.lastname: Jones
authors.forename: Maureen A
authors.initials: MA
authors.lastname: Kane
authors.forename: Alexander D
authors.initials: AD
authors.lastname: MacKerell
authors.forename: Andrew
authors.initials: A
authors.lastname: Coop
authors.forename: Rae R
authors.initials: RR
authors.lastname: Matsumoto
mesh_terms: D000701:Analgesics, Opioid / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D016466:CHO Cells; D003198:Computer Simulation; D003412:Cricetulus; D004353:Drug Evaluation, Preclinical; D004361:Drug Tolerance; D006801:Humans; D008297:Male; D051379:Mice; D008956:Models, Chemical; D015394:Molecular Structure; D009020:Morphine / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D059226:Nociceptive Pain / Q000188:drug therapy; D010147:Pain Measurement; D011485:Protein Binding; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors* / Q000235:genetics; D017473:Receptors, Opioid, kappa / Q000187:drug effects / Q000235:genetics; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000235:genetics; D013329:Structure-Activity Relationship; D013797:Thebaine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D014162:Transfection
chemical_list: C587713:4a,9-dihydroxy-7a-(hydroxymethyl)-3-methyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro(3,2-e)isoquinolin-7(7aH)-one; D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D013797:Thebaine; D009270:Naloxone; C051844:norbinaltorphimine; D009271:Naltrexone; D009020:Morphine