5-HT2C Receptor PAMs as Neurotherapeutics for Cocaine Use Disorder

5-HT2C 受体 PAM 作为可卡因使用障碍的神经治疗药物

基本信息

批准号：
9884750
负责人：
Eric A. Wold
金额：
$ 3.37万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-01 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9884750
关键词：
Abstinence Address Affinity Agonist Alcohols Allosteric Site Behavior Therapy Behavioral Binding Biological Biological Assay Calcium Cells Characteristics Chemicals Chinese Hamster Ovary Cell Clinical Cocaine Dependence Data Development Diglycerides Disease Drug Design Drug Kinetics Drug Use Disorder Exhibits Experimental Designs FDA approved Family Fluorine Fostering Functional disorder G-Protein-Coupled Receptors Goals HTR2A gene Head High Pressure Liquid Chromatography In Vitro Inositol Intervention Intuition Knowledge Lead Ligands Mass Spectrum Analysis Medial Mediating Mental disorders Metabolism Molecular Molecular Conformation NMR Spectroscopy Neurobiology Neuropharmacology Neurosciences Neurotransmitters Nicotine Opioid Organic Chemistry Pathologic Pathologic Processes Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Pharmacotherapy Phenotype Phospholipase Play Positron-Emission Tomography Pre-Clinical Model Prefrontal Cortex Property Psychostimulant dependence Public Health Radiolabeled Receptor Signaling Relapse Resolution Role Serotonin Serotonin Receptor 5-HT2B Serotonin Receptor 5-HT2C Signal Transduction Site Structure Structure-Activity Relationship System Tail Technical Expertise Therapeutic Tracer Work analog base behavioral phenotyping clinically relevant cocaine use computational chemistry counterscreen design drug candidate drug discovery drug of abuse effective intervention experience experimental study flexibility improved in vivo innovation insight instrumentation lead optimization lipophilicity novel novel lead compound positive allosteric modulator pre-clinical preclinical development preservation radioligand receptor receptor function serotonin receptor therapeutic candidate tool tripolyphosphate

项目摘要

PROJECT SUMMARY The serotonin (5-HT) neurotransmitter system comprises at least 14 distinct receptors that share topologically similar orthosteric sites, a fact that contributes to the historically difficult goal of sub-type selective modulation. Allosteric modulation of G protein-coupled receptors (GPCRs) can yield drug candidates for previously elusive receptors through targeting a structurally divergent allosteric site. Evidence suggests that dysregulated signaling of the 5-HT2C receptor underlies pathological processes implicated in numerous mental health disorders, including cocaine use disorder, which is without an FDA-approved medication. Interestingly, reduced 5-HT2C receptor signaling plays a modulatory role in stimulating relapse-related phenotypes in preclinical models of cocaine addiction, and conversely, rescuing this dysfunction may provide clinical utility to promote and maintain abstinence. We hypothesize that the rational design of novel 5-HT2C receptor positive allosteric modulators (PAMs) and optimization of 5-HT2C receptor PAM lead compounds will serve as a useful strategy to rescue pathologically decreased 5-HT2C receptor signaling and, ultimately, suppress relapse-related behavioral phenotypes. To this end, 4-alkylpiperidine-2-carboxamides were designed and synthesized in a PAM hit-to-lead discovery effort. The work resulted in the discovery of two novel lead compounds, which displayed subtype- selective functional enhancement of the 5-HT2C receptor, and lacked intrinsic agonism, in vitro. Leads, CTW0415 and CYD-6-2-1, exhibited favorable in vitro and in vivo pharmacokinetics, while a broad-panel GPCR screen confirmed selectivity. In addition, these leads maintain adequate lead-like physicochemical characteristics and represent ideal molecules upon which to build our lead optimization efforts. Our iterative strategy for 5-HT2C receptor PAM lead optimization will enable robust structure activity relationship (SAR) and will be accomplished by 1) rational design and synthesis of novel 5-HT2C receptor selective PAMs; and 2) biological characterization in a cell-based 5-HT2C receptor functional assay and pharmacological characterization in a radioligand binding assay. The proposed work will advance our knowledge of 5-HT2C receptor positive allosteric modulation and provide insight towards PAM mechanism. Additionally, the current PAM lead compounds require activity enhancements via optimization to enable development of preclinical candidates. The completion of this proposal will foster technical expertise and scientific intuition, ultimately enabling the applicant to achieve the goal of becoming an academic chemical biologist studying drug use disorders and the neuropharmacology of drugs of abuse. The applicant will gain experience in medicinal, organic and computational chemistry; neuroscience; molecular and cellular pharmacology; GPCR targeting experimental design; and the fundamentals of drug discovery in allosteric modulation, neurobiology and the psychostimulant addiction fields. Taken together, the present studies represent a high impact approach towards the discovery of neurotherapeutics for cocaine use disorder, and will generate novel tools to elucidate 5-HT2C receptor function and potential therapeutic candidates.

项目摘要 5-羟色胺（5-HT）神经递质系统至少包括14个不同的受体类似的直角地点，这一事实有助于亚型选择性调制的历史困难目标。 G蛋白偶联受体（GPCR）的变构调节可以产生以前难以捉摸的候选药物通过靶向结构发散的变构位点的受体。证据表明信号失调 5-HT2C受体的基础是与许多精神疾病有关的病理过程，包括可卡因使用障碍，该障碍没有FDA批准的药物。有趣的是，减少了5-HT2C 受体信号传导在刺激复发相关表型的临床前模型中起着调节作用可卡因成瘾，相反，营救这种功能障碍可能会提供临床实用程序来促进和维护节制。我们假设新型5-HT2C受体阳性变构调节剂的合理设计（PAMS）和5-HT2C受体PAM铅化合物的优化将成为营救的有用策略病理学上降低了5-HT2C受体信号传导，最终抑制了与复发相关的行为表型。为此，设计并在PAM-to-Lead中设计并合成了4-烷基哌啶-2-羧酰胺发现工作。这项工作导致发现了两种新型铅化合物，它们显示了亚型 - 体外缺乏固有激动剂的5-HT2C受体的选择性功能增强。线索，CTW0415 和CYD-6-2-1，体外和体内药代动力学表现出良好确认的选择性。此外，这些铅保持足够的铅样理化特征和代表建立我们的铅优化工作的理想分子。我们5-HT2C的迭代策略受体PAM铅优化将实现强大的结构活动关系（SAR），并将完成 1）新型5-HT2C受体选择性PAM的合理设计和合成； 2）生物学特征在基于细胞的5-HT2C受体功能测定和药理学表征中测定。拟议的工作将提高我们对5-HT2C受体阳性变构调制的了解，并提供对PAM机制的见识。此外，当前的PAM铅化合物需要活动通过优化的增强功能，使临床前候选者的发展。该提案的完成将培养技术专长和科学直觉，最终使申请人实现目标成为研究药物使用障碍的学术化学生物学家和药物的神经药理虐待。申请人将获得药用，有机和计算化学的经验；神经科学；分子和细胞药理学； GPCR靶向实验设计；和药物的基本面变构调节，神经生物学和精神刺激成瘾领域的发现。总的来说，目前的研究代表了发现可卡因神经疗法的高影响方法疾病，并将生成新的工具来阐明5-HT2C受体功能和潜在的治疗候选物。