Discovery of mAChR5 Modulators for Use in Rodent Models of Drug Addiction

发现用于啮齿类药物成瘾模型的 mAChR5 调节剂

基本信息

批准号：
8880514
负责人：
Carrie Kimberly Jones
金额：
$ 35.31万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8880514
关键词：
Acetylcholine Acute Address Agonist Alcohols Animal Model Attenuated Basic Science Behavioral Behavioral Model Binding Sites Bioavailable Biological Assay Brain region Calcium Cells Characteristics Chemicals Cigarette Clinical Clinical Research Cognition Complex Consumption Corpus striatum structure Coupling Data Development Dopamine Dopamine Receptor Dose Drug Addiction Drug Kinetics Drug Targeting Exhibits Fingerprint Fluorescence Generations Genetic Human Image In Vitro Individual Knockout Mice Lead Ligands Link Mammals Marijuana Dependence Mediating Metabolism Methods Midbrain structure Modeling Molecular Muscarinic Acetylcholine Receptor Neuraxis Neurobiology Neurologic Neurons Neuropharmacology Neurotransmitters Nicotine Nicotinic Receptors Nociception Nucleus Accumbens Opiates Oral Pathway interactions Patients Peripheral Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacodynamics Pharmacology Pharmacotherapy Phenotype Physiological Physiological Processes Play Prevalence Process Property Psychological reinforcement Rattus Recombinants Regulation Reporting Rewards Risk Rodent Rodent Model Role Self Administration Series Signal Transduction Site Staging Structure Substantia nigra structure Testing Therapeutic Therapeutic Intervention Translational Research Ventral Tegmental Area addiction analog anxiety-like behavior base differential expression dopaminergic neuron drug addict drug metabolism drug of abuse drug reward drug withdrawal high throughput screening in vivo in vivo Model insight man motor control novel novel strategies novel therapeutics pars compacta pre-clinical preference programs psychostimulant public health relevance receptor response small molecule tool

项目摘要

DESCRIPTION (provided by applicant): Basic and translational research ranging from animal models to pharmacological and imaging-based clinical studies of drug-addicted subjects has provided important insights into the neurobiology of addiction, resulting in the development of several investigational and approved therapeutics for patients. Yet, there remains a serious need for safe and effective drug treatments that are able to address diverse clinical addictions, as individual drugs may possess their own unique etiological fingerprint. Although the neurological mechanisms of drug addiction, and the adaptations that ensue, appear to involve many complex interactions between numerous brain regions, an overarching pathway contributing to the acute rewarding and reinforcing effects of drugs of abuse appears to involve activation of the canonical mesolimbic dopamine (DA) pathway. Indeed, antagonism of DA receptors in the nucleus accumbens (NAc), the primary structure innervated by midbrain dopaminergic neurons originating in the ventral tegmental area (VTA), severely blunts the rewarding and reinforcing effects of common drugs of abuse (e.g. psychostimulants, opiates, nicotine, and alcohol). Therefore, pharmacological modulation of drug targets that lead to inhibition of mesolimbic DA signaling has remained a focal point for strategies aimed at treating human drug addiction. Acetylcholine (ACh) is a neurotransmitter important to several physiological functions and processes in mammals, including, but not limited to nociception, motor control, and cognition. Based in part on its localization and its putative role in regulating mesolimbic and mesocortical DA circuitry, modulation of the muscarinic acetylcholine receptor subtype-5 (M5) has emerged as a potentially attractive and novel strategy for treating addiction to a wide range of drugs. In particular, studies employing the use of genetic M5-knockout mice and nonselective agonists and antagonists have implicated a role for the muscarinic receptor M5 in ACh-mediated reward and reinforcement effects of drugs of abuse. While we identified the first, and to date, only reported M5-selective ligands, the DMPK properties of these compounds rendered them unsuitable as in vivo probes. A recent high-throughput screen, employing a functional calcium fluorescence assay and recombinant M5-expressing cells, has resulted in the identification of a novel series of highly selective M5 NAMs and M5 antagonists (as well as M5 PAMs); the early in vitro and in vivo metabolism and disposition data of which indicate these series of ligands possess many characteristics common to orally bioavailable small molecules capable of engaging CNS receptors. Thus, they serve as highly promising compounds for further optimization aimed at enabling in vivo proof-of- concept studies in rodents. Moreover, they represent potential leads in the discovery of a clinical candidate for an M5 pharmacotherapy in the treatment of drug addiction.

描述（由申请人提供）：从动物模型到药物成瘾受试者的药理学和基于成像的临床研究，基础和转化研究为成瘾的神经生物学提供了重要的见解，从而开发了几种针对患者的研究和批准的治疗方法然而，仍然迫切需要能够解决不同临床成瘾问题的安全有效的药物治疗，因为个别药物可能拥有自己独特的病因学指纹。似乎涉及多个大脑之间许多复杂的相互作用，导致滥用药物的急性奖赏和强化作用的总体途径似乎涉及典型中脑边缘多巴胺（DA）途径的激活，事实上，伏隔核中 DA 受体的拮抗作用。 (NAc) 是由源自腹侧被盖区 (VTA) 的中脑多巴胺能神经元支配的主要结构，严重削弱了常见神经元的奖励和强化作用。因此，抑制中脑边缘 DA 信号传导的药物靶标的药理学调节仍然是治疗人类药物成瘾的策略的焦点。神经递质对哺乳动物的多种生理功能和过程很重要，包括但不限于伤害感受、运动控制和认知，部分基于其定位及其在调节中的假定作用。中脑边缘和中皮质 DA 回路，毒蕈碱乙酰胆碱受体亚型 5 (M5) 的调节已成为治疗多种药物成瘾的潜在有吸引力的新颖策略，特别是使用基因 M5 敲除小鼠的研究。非选择性激动剂和拮抗剂表明毒蕈碱受体 M5 在乙酰胆碱介导的药物奖赏和强化作用中发挥作用。我们鉴定了第一个也是迄今为止唯一报道的 M5 选择性配体，这些化合物的 DMPK 特性使其不适合作为体内探针，最近的高通量筛选采用功能性钙测定荧光和重组 M5 表达细胞，鉴定出一系列新型高选择性 M5 NAM 和 M5 拮抗剂（以及 M5 PAM），其早期体外和体内代谢和处置数据表明了这些配体系列；具有与中枢神经系统受体结合的口服生物可利用小分子所共有的许多特征，因此，它们是非常有前途的化合物，可用于进一步优化，旨在实现啮齿类动物的体内概念验证研究。此外，它们代表了发现的潜在线索。治疗毒瘾的 M5 药物疗法的临床候选者。