Neilan Claire L, Husbands Stephen M, Breeden Simon, Ko M C Holden, Aceto Mario D, Lewis John W, Woods James H, Traynor John R
Department of Pharmacology, University of Michigan, 1301 Medical Science Res. Bldg III, Ann Arbor, MI 48109, USA.
Eur J Pharmacol. 2004 Sep 19;499(1-2):107-16. doi: 10.1016/j.ejphar.2004.07.097.
The development of buprenorphine as a treatment for opiate abuse and dependence has drawn attention to opioid ligands that have agonist actions followed by long-lasting antagonist actions. In a search for alternatives to buprenorphine, we discovered a bridged pyrrolidinomorphinan (BU72). In vitro, BU72 displayed high affinity and efficacy for mu-opioid receptors, but was also a partial delta-opioid receptor agonist and a full kappa-opioid receptor agonist. BU72 was a highly potent and long-lasting antinociceptive agent against both thermal and chemical nociception in the mouse and against thermal nociception in the monkey. These effects were prevented by mu-, but not kappa- or delta-, opioid receptor antagonists. Once the agonist effects of BU72 had subsided, the compound acted to attenuate the antinociceptive action of morphine. BU72 is too efficacious for human use but manipulation to reduce efficacy could provide a lead to the development of a treatment for opioid dependence.
丁丙诺啡作为阿片类药物滥用和依赖的一种治疗方法的发展，已使人们将注意力投向具有激动剂作用随后是持久拮抗剂作用的阿片样物质配体。在寻找丁丙诺啡的替代物时，我们发现了一种桥连吡咯烷吗啡喃（BU72）。在体外，BU72对μ-阿片受体显示出高亲和力和效力，但也是一种部分δ-阿片受体激动剂和一种完全κ-阿片受体激动剂。BU72是一种针对小鼠热和化学伤害感受以及猴子热伤害感受的高效且持久的抗伤害感受剂。这些作用可被μ-阿片受体拮抗剂阻断，但不能被κ-或δ-阿片受体拮抗剂阻断。一旦BU72的激动剂作用消退，该化合物就会减弱吗啡的抗伤害感受作用。BU72对人类使用而言效力过高，但通过操作降低效力可能会为阿片类药物依赖治疗的开发提供线索。
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