Synthesis, modeling, and pharmacological evaluation of UMB 425, a mixed μ agonist/δ antagonist opioid analgesic with reduced tolerance liabilities.

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TitleSynthesis, modeling, and pharmacological evaluation of UMB 425, a mixed μ agonist/δ antagonist opioid analgesic with reduced tolerance liabilities.
Publication TypeJournal Article
Year of Publication2013
AuthorsHealy, JR, Bezawada, P, Shim, J, Jones, JW, Kane, MA, Mackerell, AD, Coop, A, Matsumoto, RR
JournalACS Chem Neurosci
Date Published2013 Sep 18
KeywordsAnalgesics, Opioid, Animals, CHO Cells, Computer Simulation, Cricetulus, Drug Evaluation, Preclinical, Drug Tolerance, Humans, Male, Mice, Models, Chemical, Molecular Structure, Morphine, Naloxone, Naltrexone, Narcotic Antagonists, Nociceptive Pain, Pain Measurement, Protein Binding, Receptors, Opioid, delta, Receptors, Opioid, kappa, Receptors, Opioid, mu, Structure-Activity Relationship, Thebaine, Transfection

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.

Alternate JournalACS Chem Neurosci
PubMed ID23713721
PubMed Central IDPMC3778426
Grant ListDA013583 / DA / NIDA NIH HHS / United States