Discovery and development of nociceptin receptor ligands in alcohol dependence

酒精依赖中伤害感受素受体配体的发现和开发

基本信息

批准号：
7847689
负责人：
Thomas D Bannister
金额：
$ 48.56万
依托单位：
SCRIPPS FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7847689
关键词：
Affinity Agonist Alcohol consumption Alcohol dependence Alcoholism Alcohols Amygdaloid structure Animal Model Animals Anti-Anxiety Agents Attenuated Back Basic Behavioral Science Behavioral Binding Biological Biological Assay Brain Brain region Buprenorphine Cell Nucleus Cells Chemistry Clinic Clinical Data Clinical Research Computer Analysis Data Development Disease Dose Drug Kinetics Economic Burden Electrophysiology (science)Enzymes Evaluation Family member Genetic Genetic Polymorphism Goals Human Human Genetics In Vitro Individual Ion Channel Lead Libraries Ligands Literature Mediating Methods Modeling Molecular Target Neurosciences Opioid Opioid Receptor Output Patients Pharmaceutical Chemistry Pharmacology Pharmacotherapy Physiological Probability Property Quantitative Structure-Activity Relationship Rattus Receptor Activation Receptor Cell Relapse Research Research Support Rewards Rodent Role Safety Second Messenger Systems Self Administration Self Stimulation Series Signal Transduction Societies Staging Stress Sum System Testing Therapeutic Therapeutic Agents Therapeutic Intervention Toxicology Translating Translational Research alcohol exposure alcohol research base cheminformatics counterscreen delta opioid receptor design drug discovery gamma-Aminobutyric Acid health economics hedonic in vivo interest knowledge base nociceptin nociceptin receptor novel novel therapeutics pre-clinical public health relevance radioligand receptor receptor binding receptor internalization scaffold second messenger stem tool

项目摘要

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.

描述（由申请人提供）：此应用集中在根据其对NociTeptin受体（NOP受体）的作用的潜在生物学探针和治疗剂的设计，合成和评估。我们试图确定在人NOP受体中充当部分激动剂的化合物。我们将通过从头设计和通过化学形式的NOP受体配体合成药物化学方法，并通过访问NIH的MLSCN文库的化合物来产生具有高亲和力，选择性，选择性，新型结构支架的新型化合物。化合物将在各种基于细胞的功能测定和受体结合测定中进行测试。将在药代动力学分析中进一步评估铅化合物，然后评估其在（1）大鼠中央杏仁核（CEA）GABA释放的电生理测定中，以及（2）依赖大鼠中酒精的自我管理。当前的酒精成瘾药物治疗表现出适度的功效，如今没有针对NOP受体的临床测试化合物。我们的初步结果描述了由SR-2319和SR-2039代表的新型NOP受体配体系列的鉴定，对阿片受体家族成员具有低纳米尔亲和力和选择性。这些复合脚手架以及将会创建的其他脚手架，应该证明对开发其他化合物有用。我们当前的铅化合物SR-2319，就像常用的激动剂RO64-6198一样，在奖励颅内自我刺激（ICS）范式中评估的大鼠脑刺激方面没有内在的享乐值。因此，我们认为，针对NOP受体的靶向不太可能与虐待责任有关。总而言之，我们旨在采用系统的多学科药物发现策略，以识别NOP部分激动剂，以实现酒精依赖的潜在用途。公共卫生相关性：酒精依赖和滥用代表了社会的巨大健康和经济负担，可用的药物治疗表明疗效不足。我们的目标是产生一种新型的治疗实体，用于酒精研究，并有可能最终转化为诊所作为酒精依赖和滥用的有效治疗方法。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Exploiting the co-reliance of tumours upon transport of amino acids and lactate: Gln and Tyr conjugates of MCT1 inhibitors.

利用肿瘤对氨基酸和乳酸转运的相互依赖性：MCT1 抑制剂的 Gln 和 Tyr 缀合物。

DOI：
10.1039/c5md00579e
发表时间：
2016
期刊：
MedChemComm
影响因子：
0
作者：
Nair,RejiN;Mishra,JitendraK;Li,Fangzheng;Tortosa,Mariola;Yang,Chunying;Doherty,JoanneR;Cameron,Michael;Cleveland,JohnL;Roush,WilliamR;Bannister,ThomasD
通讯作者：
Bannister,ThomasD

Dependence-induced increase of alcohol self-administration and compulsive drinking mediated by the histone methyltransferase PRDM2.

DOI：
10.1038/mp.2016.131
发表时间：
2017-12
期刊：
Molecular psychiatry
影响因子：
11
作者：
Barbier E;Johnstone AL;Khomtchouk BB;Tapocik JD;Pitcairn C;Rehman F;Augier E;Borich A;Schank JR;Rienas CA;Van Booven DJ;Sun H;Nätt D;Wahlestedt C;Heilig M
通讯作者：
Heilig M

Nociceptin receptor activation does not alter acquisition, expression, extinction and reinstatement of conditioned cocaine preference in mice.

伤害感受肽受体激活不会改变小鼠条件性可卡因偏好的获得、表达、消除和恢复。