UNIVERSITY OF MARYLAND, BALTIMORE;WEST VIRGINIA UNIVERSITY;COOP, ANDREW;MACKERELL, ALEXANDER D.;MATSUMOTO, RAE
发明人:
COOP, ANDREW,MACKERELL, ALEXANDER D.,MATSUMOTO, RAE
申请号：
CA2911681
公开号：
CA2911681A1
申请日:
2014.03.06
申请国别(地区):
CA
年份:
2014
代理人:
摘要：
An opioid narcotics used for the treatment of moderate-to-severe pain that primarily exert their analgesic effects through µ receptors. Although, traditional µ agonists can cause undesired side effects, including tolerance, addition of d antagonists 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 lacks d-specific motifs, conformationally sampled pharmacophore models for µ and d receptors predict it to have efficacy similar to morphine at µ receptors and similar to naltrexone at d receptors, due to the compound sampling conformations in which the hydroxyl moiety interacts with the receptors similar to orvinols. UMB 425 exhibits a mixed µ agonist/d antagonist profile as determined in receptor binding. UMB 425 has mixed µ agonist/d antagonist properties in vitro that translate to reduced tolerance liabilities in vivo.
