κ/μ混合型阿片受体激动剂：6β-纳曲胺类化合物
Mixed kappa/mu opioid receptor agonists: the 6 beta-naltrexamines.
作者信息
Cami-Kobeci Gerta, Neal Adrian P, Bradbury Faye A, Purington Lauren C, Aceto Mario D, Harris Louis S, Lewis John W, Traynor John R, Husbands Stephen M
机构信息
Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, United Kingdom.
出版信息
J Med Chem. 2009 Mar 26;52(6):1546-52. doi: 10.1021/jm8015552.
Abstract
Ligands from the naltrexamine series have consistently demonstrated agonist activity at kappa opioid receptors (KOR), with varying activity at the mu opioid receptor (MOR). Various 6 beta-cinnamoylamino derivatives were made with the aim of generating ligands with a KOR agonist/MOR partial agonist profile, as ligands with this activity may be of interest as treatment agents for cocaine abuse. The ligands all displayed the desired high affinity, nonselective binding in vitro and in the functional assays were high efficacy KOR agonists with some partial agonist activity at MOR. Two of the new ligands (12a, 12b) have been evaluated in vivo, with 12a acting as a KOR agonist and therefore somewhat similar to the previously evaluated analogues 3-6, while 12b displayed predominant MOR agonist activity.
摘要
纳曲胺系列的配体在κ阿片受体（KOR）上一直表现出激动剂活性，在μ阿片受体（MOR）上的活性各不相同。制备了各种6β-肉桂酰氨基衍生物，目的是生成具有KOR激动剂/MOR部分激动剂特征的配体，因为具有这种活性的配体可能作为可卡因滥用的治疗药物而受到关注。这些配体在体外均表现出所需的高亲和力、非选择性结合，在功能测定中是高效的KOR激动剂，在MOR上具有一些部分激动剂活性。其中两个新配体（12a、12b）已在体内进行了评估，12a作为KOR激动剂，因此在某种程度上类似于先前评估的类似物3-6，而12b则表现出主要的MOR激动剂活性。
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本文引用的文献
1
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J Med Chem. 2006 Oct 5;49(20):6104-10. doi: 10.1021/jm060595u.
2
Structural determinants of opioid activity in derivatives of 14-aminomorphinones: effect of substitution in the aromatic ring of cinnamoylaminomorphinones and codeinones.14-氨基吗啡酮衍生物中阿片样物质活性的结构决定因素：肉桂酰氨基吗啡酮和可待因酮芳香环取代的影响
J Med Chem. 2006 Aug 24;49(17):5333-8. doi: 10.1021/jm0604777.
3
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J Med Chem. 2003 Apr 24;46(9):1758-63. doi: 10.1021/jm021118o.
4
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J Med Chem. 2003 Apr 10;46(8):1563-6. doi: 10.1021/jm021073r.
5
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Psychopharmacology (Berl). 2001 Sep;157(2):151-62. doi: 10.1007/s002130100788.
6
Interactions between kappa opioid agonists and cocaine. Preclinical studies.κ阿片受体激动剂与可卡因之间的相互作用。临床前研究。
Ann N Y Acad Sci. 2000;909:104-32. doi: 10.1111/j.1749-6632.2000.tb06678.x.
7
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Eur J Pharmacol. 1999 Aug 13;378(3):323-30. doi: 10.1016/s0014-2999(99)00460-4.
8
9
Discovery of a structurally novel opioid kappa-agonist derived from 4,5-epoxymorphinan.从4,5-环氧吗啡喃衍生出的一种结构新颖的阿片κ激动剂的发现。
Chem Pharm Bull (Tokyo). 1998 Feb;46(2):366-9. doi: 10.1248/cpb.46.366.
10
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Eur J Pharmacol. 1997 Nov 12;338(3):215-23. doi: 10.1016/s0014-2999(97)81924-3.
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