Synthesis, modeling, and pharmacological evaluation of UMB 425, a mixed ? agonist/? 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 ? receptors. Although traditional ? agonists can cause undesired side effects, including tolerance, addition of ? 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 ?-specific motifs, conformationally sampled pharmacophore models for ? and ? receptors predict it to have efficacy similar to morphine at ? receptors and similar to naltrexone at ? 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 ? agonist/? antagonist profile as determined in receptor binding and [(35)S]GTP?S 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 ?-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 ?-specific motifs fused to the C-ring, UMB 425 has mixed ? agonist/? antagonist properties in vitro that translate to reduced tolerance liabilities in vivo.

SUBMITTER: Healy JR 

PROVIDER: S-EPMC3778426 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature