4a,9-Dihydroxy-7a-(hydroxymethyl)-3-methyl-1,2,4,5,6,13-hexahydro-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one

• 分子结构分类: 有机化合物 - 苯类化合物 - 菲及其衍生物
• 英文名称: 4a,9-Dihydroxy-7a-(hydroxymethyl)-3-methyl-1,2,4,5,6,13-hexahydro-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one
• 英文别名: 4a,9-dihydroxy-7a-(hydroxymethyl)-3-methyl-1,2,4,5,6,13-hexahydro-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one
• 化学式: C₁₈H₂₁NO₅
• 分子量: 331.4
• InChiKey: TUCMKNSLNAOLIZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.5
• 重原子数：
  24
• 可旋转键数：
  1
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.61
• 拓扑面积：
  90.2
• 氢给体数：
  3
• 氢受体数：
  6

文献信息

• [EN] NOVEL MIXED μ AGONIST/ δ ANTAGONIST OPIOID ANALGESICS WITH REDUCED TOLERANCE LIABILITIES AND USES THEREOF<br/>[FR] NOUVEAUX ANALGÉSIQUES OPIOÏDES MIXTES AGONISTES &Mgr; / ANTAGONISTES &Dgr; PRÉSENTANT MOINS D'INCONVÉNIENTS LIÉS À LA TOLÉRANCE ET LEURS UTILISATIONS
  申请人：UNIV MARYLAND

  公开号：WO2014138378A1

  公开（公告）日：2014-09-12

  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 δ 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 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. UMB 425 exhibits a mixed μ agonist/δ antagonist profile as determined in receptor binding. UMB 425 has mixed μ agonist/δ antagonist properties in vitro that translate to reduced tolerance liabilities in vivo.

  一种用于治疗中至重度疼痛的阿片类镇痛药物，主要通过μ受体发挥其镇痛作用。尽管传统的μ激动剂可能引起不良副作用，包括耐受性，但添加δ拮抗剂可以减轻这些副作用。本发明包括4a,9-二羟基-7a-(羟甲基)-3-甲基-2,3,4,4a,5,6-六氢-1 H-4,12-甲基苯并呋喃[3,2-e]异喹啉-7(7aH)-酮（UMB 425），一种基于5,14-桥联吗啡酮的奥维诺前体，以及吗啡、二氢吗啡、羟吗啡、可待因、二氢可待因、羟考酮和乙基吗啡的类似物。尽管UMB 425缺乏δ特异性基序，但μ和δ受体的构象采样药效模型预测其在μ受体上具有类似吗啡的功效，在δ受体上类似于纳曲酮，因为该化合物在构象采样中与受体相互作用的羟基部分类似于奥维诺酮。UMB 425在受体结合中表现出混合的μ激动剂/δ拮抗剂特性。UMB 425在体外表现出混合的μ激动剂/δ拮抗剂特性，这在体内转化为降低的耐受性风险。
• NOVEL MIXED μ AGONIST/ δ ANTAGONIST OPIOID ANALGESICS WITH REDUCED TOLERANCE LIABILITIES AND USES THEREOF
  申请人：COOP Andrew

  公开号：US20160016965A1

  公开（公告）日：2016-01-21

  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 δ antagonists can attenuate said side effects. The present invention includes 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, along with analogs of morphine, dihydromorphine, hydromorphone, codeine, dihydrocodeine, hydrocodone and ethylmorphine. 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. UMB 425 exhibits a mixed μ agonist/δ antagonist profile as determined in receptor binding. UMB 425 has mixed μ agonist/δ antagonist properties in vitro that translate to reduced tolerance liabilities in vivo.

  一种阿片类麻醉药物，用于治疗中度到重度疼痛，主要通过μ受体发挥其镇痛作用。尽管传统的μ激动剂可能会引起不良反应，包括耐受性，但加入δ拮抗剂可以减轻这些不良反应。本发明包括4a，9-二羟基-7a-（羟甲基）-3-甲基-2，3，4，4a，5，6-六氢-1H-4，12-甲烷基苯并呋喃[3，2-e]异喹啉-7（7aH）-酮（UMB 425），一种基于5,14-桥接吗啡的奥维诺前体，以及吗啡，二氢吗啡，羟吗啡，可待因，二氢可待因，氢可酮和乙基吗啡的类似物。虽然UMB 425缺乏δ特异性基序，但μ和δ受体的构象采样药效模型预测其在μ受体上具有类似吗啡的功效，在δ受体上具有类似于纳曲酮的功效，因为化合物采样与奥维诺尔类似的构象，其中羟基部分与受体相互作用。UMB 425在受体结合中表现出混合的μ激动剂/δ拮抗剂特性。UMB 425在体外表现出混合的μ激动剂/δ拮抗剂特性，这种特性在体内可转化为降低耐受性的效果。
• NOVEL MIXED AGONIST/ ANTAGONIST OPIOID ANALGESICS WITH REDUCED TOLERANCE LIABILITIES AND USES THEREOF
  申请人：University of Maryland, Baltimore

  公开号：EP2964228A1

  公开（公告）日：2016-01-13
• NOVEL MIXED AGONIST/ANTAGONIST OPIOID ANALGESICS WITH REDUCED TOLERANCE LIABILITIES AND USES THEREOF
  申请人：University of Maryland, Baltimore

  公开号：EP2964228B1

  公开（公告）日：2019-05-08
• US9422302B2
  申请人：——

  公开号：US9422302B2

  公开（公告）日：2016-08-23