Discovery and development of nociceptin receptor ligands in alcohol dependence

描述(由申请人提供)：本申请的重点是设计、合成和评估潜在的生物探针和酒精依赖治疗药物，基于它们对伤害素受体(NOP受体)的作用。我们试图确定在人类NOP受体上起部分激动剂作用的化合物。我们将利用药物化学的方法，通过从头设计和合成假定的NOP受体配体，通过化学信息学的努力，并通过访问NIH的MLSCN库中的化合物来生成具有高亲和力、选择性和新的结构支架的新化合物。化合物将在各种基于细胞的功能分析和受体结合分析中进行测试。先导化合物将在药代动力学分析中进一步评估，然后评估它们在(1)大鼠中央杏仁核(CEA)GABA释放的电生理学测定和(2)依赖大鼠自身给药酒精方面的有效性。目前的酒精成瘾药物治疗已显示出中等疗效，目前还没有针对NOP受体的临床可测试化合物存在。我们的初步结果描述了以SR-2319和SR-2039为代表的一个新的、可申请专利的NOP受体配体系列的鉴定，该系列与阿片受体家族成员相比具有低的纳摩尔亲和力和选择性。这些复合支架和其他将被创建的支架应该被证明对开发更多的化合物是有用的。我们目前的先导化合物SR-2319，与常用的激动剂Ro64-6198一样，在脑刺激奖赏方面并不具有内在的享乐学价值，如在颅内自我刺激(ICSS)范式中所评估的那样。因此，我们认为以NOP受体为靶点不太可能与滥用责任有关。综上所述，我们的目标是采取系统和多学科的药物发现策略，寻找可能用于酒精依赖治疗的NOP部分激动剂(S)。与公共卫生相关：酒精依赖和滥用给社会带来了相当大的健康和经济负担，现有的药物疗法显示疗效不足。我们的目标是产生一种新的治疗实体，用于酒精研究，并有可能最终转化为临床，作为酒精依赖和滥用的有效治疗方法。

DESCRIPTION (provided by applicant): This application is focused on the design, synthesis and evaluation of potential biological probes and treatment agents for alcohol dependence based on their actions on the nociceptin receptor (NOP receptor). We seek to identify compounds that act as partial agonists at the human NOP receptor. We will utilize a medicinal chemistry approach via de novo design and synthesis of putative NOP receptor ligands through cheminformatics efforts and by accessing compounds from the NIH's MLSCN library to generate novel compounds with high affinity, selectivity, and novel structural scaffolds. Compounds will be tested in various cell-based functional assays and in receptor binding assays. Lead compounds will be further evaluated in pharmacokinetic analyses followed by assessment of their efficacies in (1) electrophysiological assay of rat central amygdala (CeA) GABA release and (2) self-administration of alcohol in dependent rats. Current alcohol addiction pharmacotherapies have shown moderate efficacy and no clinically testable compounds targeting the NOP receptor are in existence today. Our preliminary results describe the identification of a novel and patentable NOP receptor ligand series represented by SR-2319 and SR-2039, with low nanomolar affinity and selectivity over opioid receptor family members. These compound scaffolds, and others that will be created, should prove useful for the development of additional compounds. Our current lead compound, SR-2319, like the commonly used agonist Ro64-6198, does not possess intrinsic hedonic value in rewarding brain stimulation in rats as evaluated in the intracranial self-stimulation (ICSS) paradigm. We therefore believe that targeting of the NOP receptor will not likely be associated with abuse liability. In sum, we aim to take a systematic and multi-disciplinary drug discovery strategy to identify NOP partial agonist(s) for the potential use in alcohol dependence. PUBLIC HEALTH RELEVANCE: Alcohol dependence and abuse represents a considerable health and economic burden on society with available pharmacotherapies demonstrating insufficient efficacy. Our goal is to generate a novel therapeutic entity to be used in alcohol research and with the potential of ultimately translating into the clinic as efficacious treatments for alcohol dependence and abuse.