CB1 Allosteric Modulators: Molecular, Cellular and In Vivo Pharmacology

CB1 变构调节剂：分子、细胞和体内药理学

基本信息

批准号：
9056090
负责人：
DEBRA A KENDALL
金额：
$ 53.39万
依托单位：
UNIVERSITY OF CONNECTICUT STORRS
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-15 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9056090
关键词：
2-arachidonylglycerol Active Sites Adverse effects Affinity Agonist Amides Animal Model Arrestins Attenuated Behavior Behavioral Model Binding Binding Sites Biochemistry Biological Biological Assay Biology Brain CNR1 gene CNR2 gene Cannabinoids Cannabis sativa plant Central Nervous System Diseases Complex Coupled Coupling Development Disease Dissociation Drug Addiction Drug abuse Eating Disorders Endocannabinoids Equilibrium Feeding behaviors G-Protein-Coupled Receptors GTP-Binding Proteins Goals Incidence Indoles Inflammation Knowledge Laboratories Lead Ligand Binding Ligands Mediating Memory Metabolic syndrome Molecular Molecular Profiling Mus Neuraxis Nicotine Outcome Outcome Study Pain Pathway interactions Pattern Pharmaceutical Chemistry Pharmacology Phosphorylation Physiological Processes Plants Process Property Regulation Research Rewards Signal Pathway Signal Transduction Site Structure-Activity Relationship Substance Addiction Substance abuse problem Synaptic Transmission System Testing Therapeutic Therapeutic Agents Translating Work anandamide base behavioral pharmacology cannabimimetics cannabinoid receptor design drug discrimination energy balance feeding functional group improved in vivo mRNA Expression mouse model novel painful neuropathy positive allosteric modulator public health relevance pyridine receptor response scaffold targeted treatment therapeutic target

项目摘要

DESCRIPTION (provided by applicant): The cannabinoid receptor CB1 is a G-protein coupled receptor (GPCR) that regulates neural transmission and other physiological processes. CB1 is activated by endogenous ligands (e.g. arachidonoyl ethanolamide (AEA) and 2-arachidonoyl glycerol (2-AG)) and various synthetic and plant-derived ligands that bind to the receptor orthosteric site. These CB1 orthosteric ligands transduce signals to downstream effectors primarily via Gi/o coupling, but Gs and arrestin coupling are also possible. The biological responses are implicated in many therapeutic applications, such as substance addiction, pain and inflammation, memory, and feeding and energy balance. Recently, allosteric modulators for GPCRs were discovered. Whereas positive allosteric modulators (PAMs) enhance the functional efficacy of orthosteric agonists, negative allosteric modulators (NAMs) non-competitively decrease the activity of the receptor. These modulators bind GPCR regions topographically distinct from the orthosteric ligand binding sites and thereby exert their modulatory effects in a highly subtype specific manner. CB1 NAMs offer exciting opportunities for developing therapeutics for drug addiction and metabolic syndromes and PAMs open a new pathway to treat pain-related conditions with a reduced incidence of unwanted psychotropic effects. However, the underlying mechanisms for CB1 allosteric modulation, including for allosteric-modulation biased downstream signaling, remain elusive. We have designed and synthesized highly potent PAMs, such as LDK 1256 (KB = 89 nM), and with high allostery, such as LDK1258 (=24.5), for enhanced agonist binding. We also have identified NAMs that are the only known modulators for reducing agonist binding to CB1. We have discovered that the CB1 allosteric modulator ORG27569 is coupled to an arrestin signaling pathway, which represents the first example of a CB1 biased allosteric modulator. In this project, we will synthesize compounds through optimizing the properties of identified allosteric modulators, develop new scaffolds and identify pharmacophoric groups that improve the equilibrium dissociation constants and cooperativity factors. These compounds will be tested for impact on agonist and inverse agonist binding. We will also elucidate their G-protein and arrestin coupling and downstream molecular-level activities. In an iterative process, key CB1 modulators will be fine tuned via structure-activity relationship (SAR) analysis. We will evaluate potent allosteric modulators for their impact on CB1 pharmacological responses in vivo. This effort involves assessing key CB1 allosteric modulators versus orthosteric compounds in functional assays including in the cannabinoid tetrad and drug discrimination assays. We will also test lead ligands in mouse models of neuropathic pain, feeding, and nicotine reward. The overall goal of this work is to identify new PAMs and NAMs, elucidate their molecular level profiles, and test lead ligands in animal models. These efforts are critical for elucidating the basis of CB1 allosteric modulation so that ultimately highly specific responses can be attained via therapeutic agents.

描述（由适用提供）：大麻素受体CB1是调节神经传播和其他物理过程的G蛋白偶联受体（GPCR）。 CB1被内源配体（例如Arachidonoyl乙醇酰胺（AEA）和2-芳烃甘油（2-AG））以及各种合成和植物衍生的配体与受体正骨位点结合。这些CB1正常配体通过GI/O耦合将信号传递至下游效应，但GS和阻止蛋白偶联也是可能的。生物学反应在许多治疗应用中实施，例如添加物质，疼痛和注射，记忆以及喂养和能量平衡。最近，发现了用于GPCR的变构调节剂。阳性变构调节剂（PAMS）增强了直角激动剂的功能有效性，而负变构调节剂（NAMS）非竞争地降低接收器的活性。这些调节剂结合了GPCR区域在地形上与正常配体结合位点不同，从而以高度亚型的特定方式执行其调节作用。 CB1 NAMS为开发药物成瘾和代谢综合症的治疗提供了令人兴奋的机会，而PAM则为治疗与疼痛有关的疾病开辟了新的途径，并降低了不必要的精神效应。但是，CB1变构调制的基本机制（包括偏向下游信号传导）仍然难以捉摸。我们已经设计和合成了高潜力的PAM，例如LDK 1256（Kb = 89 nm），并具有高变构（例如LDK1258（= 24.5）），以增强激动剂的结合。我们还确定了NAM，这些NAM是唯一已知的调节剂，用于减少与CB1结合的激动剂。我们发现CB1变构调节剂ORG27569耦合到逮捕蛋白信号通路，这是CB1偏置变构调节剂的第一个例子。在这个项目中，我们将通过优化已识别的变构调节剂的性能，开发新的脚手架并确定改善等效分离常数和协调因子的药物群来合成化合物。这些化合物将经过对激动剂和反向激动剂结合的影响。我们还将阐明他们的G蛋白和阻止素耦合以及下游分子级活动。在迭代过程中，将通过结构活性关系（SAR）分析对关键CB1调节剂进行微调。我们将评估潜在的变构调节剂对体内CB1药物反应的影响。这项工作涉及评估功能测定中的关键CB1变构调节剂与直角化合物，包括在大麻素四局和药物辨别术中。我们还将在神经性疼痛，喂养和尼古丁奖励的小鼠模型中测试铅配体。这项工作的总体目标是识别新的PAM和NAM，阐明其分子水平谱以及动物模型中的测试铅配体。这些努力对于阐明CB1变构调制的基础至关重要因此，最终可以通过治疗剂附加高度特定的反应。