Ebert B, Andersen S, Krogsgaard-Larsen P
Department of Medicinal Chemistry, Royal Danish School of Pharmacy, Copenhagen O, Denmark.
Neurosci Lett. 1995 Mar 10;187(3):165-8. doi: 10.1016/0304-3940(95)11364-3.
The opiate agonists, ketobemidone, methadone and pethidine, were evaluated as N-methyl-D-aspartate (NMDA) receptor antagonists using the rat cortical wedge preparation and the neonatal rat spinal cord preparation for electrophysiological studies and 3H-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-im ine ([3H]MK-801) binding experiments using rat forebrain homogenates. Ketobemidone, methadone and pethidine were inhibitors of [3H]MK-801 binding with Ki values of 26 microM, 0.85 microM and 47 microM, respectively. In the cortex, 1 mM ketobemidone and 1 mM methadone reduced NMDA responses, but not (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propionic acid (AMPA) or kainate responses in an use-dependent manner, whereas 1 mM pethidine was devoid of antagonist activity. In the spinal cord preparation, the activities of ketobemidone and methadone were weaker than in cortex. In contrast, pethidine was equipotent with ketobemidone in the spinal cord. These results suggest that ketobemidone and methadone may be useful therapeutic agents in conditions where a combined opiate agonist and NMDA antagonist treatment is desired.
使用大鼠皮质楔形标本和新生大鼠脊髓标本进行电生理研究，并利用大鼠前脑匀浆进行3H-5-甲基-10,11-二氢-5H-二苯并[a,d]环庚烯-5,10-亚胺([3H]MK-801)结合实验，对阿片类激动剂凯托米酮、美沙酮和哌替啶作为N-甲基-D-天冬氨酸(NMDA)受体拮抗剂进行了评估。凯托米酮、美沙酮和哌替啶是[3H]MK-801结合的抑制剂，其Ki值分别为26μM、0.85μM和47μM。在皮质中，1 mM凯托米酮和1 mM美沙酮以使用依赖的方式降低NMDA反应，但不降低(RS)-2-氨基-3-(3-羟基-5-甲基异恶唑-4-基)丙酸(AMPA)或海人藻酸反应，而1 mM哌替啶没有拮抗活性。在脊髓标本中，凯托米酮和美沙酮的活性比在皮质中弱。相比之下，哌替啶在脊髓中的活性与凯托米酮相当。这些结果表明，在需要联合使用阿片类激动剂和NMDA拮抗剂治疗的情况下，凯托米酮和美沙酮可能是有用的治疗药物。
