Kumar Vinod, Polgar Willma E, Cami-Kobeci Gerta, Thomas Mark P, Khroyan Taline V, Toll Lawrence, Husbands Stephen M
Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, India.
SRI International, Menlo Park, CA, United States.
Front Psychiatry. 2018 Sep 19;9:430. doi: 10.3389/fpsyt.2018.00430. eCollection 2018.
A series of 14β-acyl substituted 17-cyclopropylmethyl-7,8-dihydronoroxymorphinone compounds has been synthesized and evaluated for affinity and efficacy for mu (MOP), kappa (KOP), and delta (DOP) opioid receptors and nociceptin/orphanin FQ peptide (NOP) receptors. The majority of the new ligands displayed high binding affinities for the three opioid receptors, and moderate affinity for NOP receptors. The affinities for NOP receptors are of particular interest as most classical opioid ligands do not bind to NOP receptors. The predominant activity in the [S]GTPγS assay was partial agonism at each receptor. The results are consistent with our prediction that an appropriate 14β side chain would access a binding site within the NOP receptor and result in substantially higher affinity than displayed by the parent compound naltrexone. Molecular modeling studies, utilizing the recently reported structure of the NOP receptor, are also consistent with this interpretation.
已合成了一系列14β-酰基取代的17-环丙基甲基-7,8-二氢诺氧吗啡酮化合物，并对其与μ（MOP）、κ（KOP）和δ（DOP）阿片受体以及孤啡肽/孤啡肽FQ肽（NOP）受体的亲和力和效力进行了评估。大多数新配体对三种阿片受体表现出高结合亲和力，对NOP受体表现出中等亲和力。由于大多数经典阿片配体不与NOP受体结合，因此对NOP受体的亲和力特别令人感兴趣。在[S]GTPγS试验中的主要活性是在每个受体上的部分激动作用。结果与我们的预测一致，即合适的14β侧链将进入NOP受体内的一个结合位点，并导致比母体化合物纳曲酮更高的亲和力。利用最近报道的NOP受体结构进行的分子模拟研究也与这种解释一致。
