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:
- 金额:$ 63.53万
- 依托单位:
- 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:
- 关键词:AcuteAgonistAlcohol abuseAlcohol consumptionAlcohol dependenceAlcoholismAlcoholsAnimal ModelAnxietyArousalAttenuatedBehaviorBehavioralBindingBioavailableBiological AssayBiological AvailabilityBlood - brain barrier anatomyBrainCell LineCellsChinese Hamster Ovary CellChronicClinicalComplementComputer AnalysisCuesCyclic AMPDataDevelopmentDiseaseDoseDrug KineticsEatingEvaluationFamilyG-Protein-Coupled ReceptorsGoalsHomology ModelingIn VitroInjectionsKnockout MiceLeadLigandsLinkLocomotionMessenger RNAMetabolicModificationMotor ActivityNaltrexoneNamesNeuropeptidesPatientsPeptidesPeripheralPermeabilityPharmaceutical ChemistryPharmaceutical PreparationsPharmacologyPharmacotherapyPlasmaPlayPropertyRattusRelapseRelaxinResearchRoleRouteSelf AdministrationSeriesStressStructure-Activity RelationshipSucroseSystemTestingTherapeuticTherapeutic Agentsacamprosatealcohol abuse therapyalcohol behavioralcohol effectalcohol preferring ratsalcohol reinforcementalcohol relapsealcohol seeking behavioralcohol testingalcohol use disorderalcoholism therapyanalogbasebehavioral phenotypingbehavioral studybiological adaptation to stressdesignhazardous drinkinghigh throughput screeningin silicoin vivoinhibitor/antagonistintraperitonealmedication compliancenew therapeutic targetnovelnovel therapeuticspharmacophorepreferencepreventproblem drinkerprocedural memoryradioligandreceptorscaffoldscreeningside effectsmall moleculestress reductiontool
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
项目成果
期刊论文数量(0)
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JOYCE BESHEER其他文献
JOYCE BESHEER的其他文献
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