In vitro and in vivo characterization of CB1 allosteric modulators

CB1变构调节剂的体外和体内表征

基本信息

批准号：
10201542
负责人：
Thomas F Gamage
金额：
$ 16.84万
依托单位：
RESEARCH TRIANGLE INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10201542
关键词：
2-arachidonylglycerol Affect Affinity Agonist Antibodies Attenuated Award Behavior Behavioral Behavioral Assay Behavioral Model Binding Biological Biological Assay Budgets CNR1 gene CNR2 gene Cannabinoids Cells Chemicals Clinical Clinical Data Complex Coupling Data Development Disease Dronabinol Drug Addiction Drug Targeting Drug abuse Educational workshop Endocannabinoids Enhancers Exhibits Feeling suicidal Funding GTP Binding GTP-Binding Proteins Goals In Vitro K-Series Research Career Programs Laboratories Learning Ligand Binding Ligands Mental Depression Mentors Metabolic syndrome Modeling Modification Molecular Molecular Biology Molecular Conformation Mus Neuraxis New England Obesity Opioid Pain Parents Pharmaceutical Preparations Pharmacology Pharmacology Study Pharmacotherapy Physiological Pre-Clinical Model Principal Investigator Receptor Signaling Reporting Research SR141716 Self Administration Signal Pathway Signal Transduction Signaling Protein Site Structure Structure-Activity Relationship Techniques Testing Therapeutic Training addiction analog anandamide antagonist G base cannabinoid receptor career development clinically relevant experimental study improved in vivo induced hypothermia novel opioid abuse opioid withdrawal pre-clinical programs radioligand receptor response responsible research conduct rimonabant scaffold side effect small molecule stoichiometry success synthetic cannabinoid targeted treatment theories therapeutic target vector

项目摘要

The cannabinoid type-1 (CB1) receptor is a promising pharmacotherapeutic target for many diseases as evidenced by a large body of preclinical and clinical data showing efficacy treating drug dependence/addiction, pain, obesity/metabolic syndrome, and others. Unfortunately drugs developed that target the CB1 receptor either directly or indirectly have had limited success, i.e. dronabinol produces undesired psychoactivity, rimonabant produces depression/suicidal ideation, and PF-04457845 did not demonstrate efficacy. Important considerations in the therapeutic vs. nontherapeutic effects of CB1 activation are the various signaling pathways that contribute to either of these. Allosteric modulation provides an additional vector through which the CB1 receptor can be manipulated for therapeutic gain. This study proposes to 1) examine novel structural analogs of established CB1 allosteric modulators for their ability to alter orthosteric ligand binding, function, and signaling bias; 2) characterize G protein subtype-dependent coupling by orthosteric and allosteric ligands in N18TG2 cells which provide physiologically relevant receptor/G protein stoichiometry; and 3) assess the effects of CB1 allosteric modulators in assays of cannabinoid activity, opioid withdrawal and self-administration for determination of efficacy in therapeutically relevant models. My goals for this career development award are to build on my laboratory’s capabilities and prepare for independence as a principal investigator in the behavioral and molecular pharmacology of drug abuse. My laboratory currently has the capabilities to carry out the proposed studies but I require additional training in molecular pharmacology to learn G protein antibody capture scintillation proximity assay to complete Aim 2 which I will learn in Dr. Allyn Howlett’s laboratory. I will also learn complementary techniques in molecular biology in a workshop from New England BioLabs. I will also benefit from guidance in receptor theory, application of allosteric models and quantification of signaling bias which I will receive from my co-mentor Dr. Terry Kenakin. I also require training in self-administration for Aim 3 experiments which I will learn in Dr. Jenny Wiley’s laboratory. In addition to technical training, I require career development in order prepare for research independence. Under this award I will receive training in grantsmanship, laboratory management, budget management, and responsible conduct of research. These career development activities will include one-on-one training with co-mentors as well as workshops to provide me with necessary training to successfully compete for R01 funding and develop a highly productive and efficient independent research program.

大麻素类型1（CB1）受体是许多疾病的有前途的药物治疗靶标大量的临床前和临床数据显示出有效性治疗药物依赖/成瘾，疼痛，肥胖/代谢综合征等。不幸的是开发了针对CB1受体的药物直接或间接取得了有限的成功，即Dronabinol会产生Une -deSired Issired，Rimonabant 产生抑郁症/杀虫剂的想法，PF-04457845并未表现出效率。重要的考虑因素在CB1激活的治疗和非治疗效应中，有助于这两个。变构调制提供了一个额外的矢量，CB1受体可以通过该载体为治疗收益而操纵。这项研究提案1）检查已建立的CB1的新结构类似物变构调节剂具有改变正常配体结合，功能和信号传导偏置的能力； 2）表征G蛋白亚型依赖性偶联的N18TG2细胞中的正构和变构配体的偶联提供物理相关的受体/G蛋白化学计量； 3）评估CB1变构的影响调节剂大麻素活性，阿片类药物戒断和自我管理的调节剂用于确定在治疗相关模型中有效。我这个职业发展奖的目标是建立在我的基础上实验室的能力，并为行为和分子的主要研究者做准备独立药物滥用药理学。我的实验室目前有能力进行拟议的研究，但我需要在分子药理学上进行额外的培训，以学习G蛋白抗体捕获闪烁接近度测定完成AIM 2的测定，我将在Allyn Howlett博士的实验室中学到。我也会学习完整来自新英格兰Biolabs的研讨会中分子生物学的技术。我还将受益于指导接收器理论，变构模型的应用和信号偏差的数量，我将从我的联盟人特里·基金博士。我还需要对AIM 3实验进行自我管理的培训，我将学习在珍妮·威利（Jenny Wiley）博士的实验室中。除技术培训外，我还需要职业发展以准备用于研究独立性。根据该奖项，我将获得授予技巧，实验室管理的培训，预算管理和负责任的研究。这些职业发展活动将包括与联合会员的一对一培训，以及为我提供必要的培训以成功的培训竞争R01资金并制定高效，高效的独立研究计划。