Synthesis Modeling and Pharmacological Evaluationof UMB 425 a Mixed μ Agonist/δ Antagonist Opioid Analgesicwith Reduced Tolerance Liabilities

摘要

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 [³⁵S]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 notby the κ-selective antagonist norbinaltorphimine. During a 6-daytolerance paradigm, UMB 425 maintains significantly greater antinociceptioncompared to morphine. These studies thus indicate that, even in theabsence of δ-specific motifs fused to the C-ring, UMB 425 hasmixed μ agonist/δ antagonist properties in vitro thattranslate to reduced tolerance liabilities in vivo.