5‐HT2CR ALLOSTERIC MODULATORS AS NOVEL PHARMACOTHERAPY IN COCAINE USE DISORDER

5-HT2CR 变构调节剂作为可卡因使用障碍的新型药物治疗

• 批准号: 9480142
• 负责人: Kathryn A. Cunningham
• 金额: $ 0.85万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9480142
• 关键词: Address; Affinity; Agonist; Allosteric Site; Animal Model; Behavior; Behavioral; Behavioral Model; Binding; Biological Assay; Biological Availability; Brain; Categories; Cells; Cellular Assay; Chemicals; Cocaine; Coupled; Cues; Data; Dependence; Development; Disease; Dose; Drug Kinetics; Drug usage; Engineering; Ensure; Evaluation; Exhibits; Family member; G-substrate; GTP-Binding Proteins; Genetic; Goals; Grant; Head; Health; Impulsivity; In Vitro; Investigation; Knowledge; Legal patent; Life; Ligands; Medial; Mediating; Medical; Mental disorders; Methods; Mission; Modeling; Motor Activity; Neurobiology; Obesity; Oral; Patients; Penetration; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phenotype; Prefrontal Cortex; Public Health; Rattus; Reaction; Recovery; Relapse; Reporting; Research; Research Project Grants; Rodent Model; Serotonergic System; Serotonin; Serotonin Receptor 5-HT2C; Sexual Dysfunction; Signal Transduction; Site; Specificity; Stimulus; System; Tail; Therapeutic; Translational Research; Treatment Efficacy; United States; United States National Institutes of Health; Urinary Incontinence; Validation; Viral; addiction; attentional bias; base; behavioral study; burden of illness; clinical application; cocaine use; cognitive process; cue reactivity; design; drug discrimination; drug metabolism; experimental study; improved; in vivo; innovation; lipophilicity; multidisciplinary; novel; novel strategies; novel therapeutics; positive allosteric modulator; pre-clinical; programs; protein expression; psychologic; public health relevance; radioligand; receptor; relating to nervous system; response; scaffold; small molecule; success

 DESCRIPTION (provided by applicant): Cocaine use disorder remains a significant health problem in the United States, and effective and safe pharmacotherapeutic approaches are urgently needed to maximize treatment success and minimize lapses to drug use. The cycling course of cocaine use disorder is tied to a multitude of behavioral and cognitive processes with impulsivity (rapid unplanned reactions to stimuli without regard for the consequences) and cue reactivity (attentional bias toward cocaine-associated cues) cited as two key phenotypes that set up vulnerability to relapse even years into recovery. The serotonin (5-HT) system provides modulatory control over impulsivity and cue reactivity, particularly through the G protein-coupled 5-HT2C receptor (5-HT2CR). Data suggest that dampened 5- HT2CR signaling capacity may contribute to phenotypic vulnerability to relapse and that normalization of 5-HT2CR tone may be useful to suppress relapse promoted by impulsivity and cue reactivity. We hypothesize that a small molecule positive allosteric modulator (PAM) of the 5-HT2CR that augments the response to endogenous 5-HT and/or an exogenous 5-HT2CR orthosteric ligand is a novel strategy to restore 5-HT2CR function. The present grant is built upon our progress in the rational design, synthesis and pharmacological evaluation of new chemical entities based upon the only reported selective 5-HT2CR PAM PNU-69176E. We have synthesized new small molecules (e.g., CYD-1-79, CYD-3-30, CYD-6-16-2) which exhibit initial profiles as 5-HT2CR PAMs (functional signaling in live cells, radioligand binding assays) and reasonable oral and brain bioavailability. In vivo behavioral studies demonstrated that CYD-1-79, at doses that do not affect general motor activity, enhanced the effects of a selective 5-HT2CR agonist in drug discrimination analyses, and suppressed impulsivity and cue reactivity in rats, indicating efficacy in primary animal models pertinent to relapse in cocaine use disorder. Our objective is to optimize 5-HT2CR PAMs with a favorable drug metabolism and pharmacokinetics (DMPK) profile, and analyze select molecules in proof-of-concept behavioral models to support therapeutic potential for cocaine use disorder. To accomplish our objective, we will: (1) design, synthesize and optimize 5-HT2CR PAMs; (2) define selectivity and specificity and DMPK profiles of 5-HT2CR PAMs in vitro; and (3) determine DMPK in vivo and efficacy of optimized 5-HT2CR PAMs in rodent models of impulsivity and cue reactivity. This innovative, potentially high impact small molecule development project will elucidate important new information about the chemical neurobiology of 5-HT2CR allosteric modulation, and drive new concepts and directions in cocaine use disorder and anti-relapse medications.