Novel mixed mu agonist/ delta antagonist opioid analgesics with reduced tolerance liabilities and uses thereof

摘要

An opioid narcotics used for the treatment of moderate-to-severe pain that primarily exert their analgesic effects throughμreceptors. Although, traditionalμagonists can cause undesired side effects, including tolerance, addition ofδantagonists can attenuate said side effects. The present invention includes 4a,9-dihydroxy-7a-(hydroxymethyl)-3 -methyl-2,3,4,4a,5,6-hexahydro-1 H-4, 12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one (UMB 425) a 5,14-bridged morphinan-based orvinol precursor, along with analogs of morphine, dihydromorphine, hydromorphone, codeine, dihydrocodeine, hydrocodone and ethylmorphine. Although UMB 425 lacksδ-specific motifs, conformationally sampled pharmacophore models forμandδreceptors predict it to have efficacy similar to morphine atμreceptors and similar to naltrexone atδreceptors, due to the compound sampling conformations in which the hydroxyl moiety interacts with the receptors similar to orvinols. UMB 425 exhibits a mixedμagonist/δantagonist profile as determined in receptor binding. UMB 425 has mixedμagonist/δantagonist properties