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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.