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Small molecule antagonist probes for the relaxin-3/RXFP3 system

松弛素 3/RXFP3 系统的小分子拮抗剂探针

基本信息

批准号：
10266756
负责人：
JOYCE BESHEER
金额：
$ 63.53万
依托单位：
RESEARCH TRIANGLE INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-20 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10266756
关键词：
Acute Agonist Alcohol abuse Alcohol consumption Alcohol dependence Alcoholism Alcohols Animal Model Anxiety Arousal Attenuated Behavior Behavioral Binding Bioavailable Biological Assay Biological Availability Blood - brain barrier anatomy Brain Cell Line Cells Chinese Hamster Ovary Cell Chronic Clinical Complement Computer Analysis Cues Cyclic AMP Data Development Disease Dose Drug Kinetics Eating Evaluation Family G-Protein-Coupled Receptors Goals Homology Modeling In Vitro Injections Knockout Mice Lead Ligands Link Locomotion Messenger RNA Metabolic Modification Motor Activity Naltrexone Names Neuropeptides Patients Peptides Peripheral Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Pharmacotherapy Plasma Play Property Rattus Relapse Relaxin Research Role Route Self Administration Series Stress Structure-Activity Relationship Sucrose System Testing Therapeutic Therapeutic Agents acamprosate alcohol abuse therapy alcohol behavior alcohol effect alcohol preferring rats alcohol reinforcement alcohol relapse alcohol seeking behavior alcohol testing alcohol use disorder alcoholism therapy analog base behavioral phenotyping behavioral study biological adaptation to stress design hazardous drinking high throughput screening in silico in vivo inhibitor/antagonist intraperitoneal medication compliance new therapeutic target novel novel therapeutics pharmacophore preference prevent problem drinker procedural memory radioligand receptor scaffold screening side effect small molecule stress reduction tool

项目摘要

The goal of this project is to develop and test small-molecule antagonist probes of the relaxin-3/RXFP3 system for behavioral studies in alcohol addiction and relapse. Alcohol addiction is a heterogeneous, chronic relapsing disorder. Current therapies are inadequate, and therefore new medications based on novel targets are needed. The recently deorphanized relaxin-3/RXFP3 system comprises the endogenous neuropeptide relaxin-3 and its cognate G protein-coupled receptor RXFP3. Multiple lines of evidence suggest that RXFP3 antagonism is a novel target for therapeutics to treat alcohol addiction and relapse. Although RXFP3 antagonist peptides are available, there are unmet needs for non-peptide small-molecule antagonists, which are systemically bioavailable and can penetrate the blood-brain barrier, to further validate the relaxin-3/RXFP3 system as a novel drug target. To date, our group has made significant progress in this regard. We have developed a stable RXFP3 cell-based cAMP high-throughput screening assay and completed a screening campaign to identify antagonist hits. Focused structure-activity relationship studies of the hit compound have resulted in the first series of small-molecule antagonists that have Ke <500 nM and are highly selective for RXFP3 over another receptor subtype RXFP1 and can penetrate into the brain. In this application, we propose to further refine our early lead-like compounds to produce antagonist probes for in vivo studies through three iterative specific aims. In Aim 1, we will optimize potency, receptor selectivity, and drug-like properties of RXFP3 antagonists using medicinal chemistry. In Aim 2, we will characterize compounds using an RXFP3 functional cAMP assay and a radioligand binding assay. Select compounds will be assessed for receptor selectivity against RXFP1 and RXFP4, two subtypes of the relaxin family, and further evaluated in a target profiling screen. Potent and selective compounds will then be characterized using a battery of ADME and pharmacokinetic assays. In Aim 3, we will test the best compounds, developed in Aims 1 and 2, in animal models of alcohol reinforcement and stress-induced reinstatement. Overall, completion of this project will provide in vivo antagonist probes to pharmacologically validate the relaxin-3/RXFP3 system as a novel target for treatment of alcoholism.

该项目的目标是开发和测试松弛素-3/RXFP3系统的小分子拮抗剂探针