Serotonin 5HT2C Agonist Drugs with 5HT2A/2B Antagonist Activity

具有 5HT2A/2B 拮抗活性的血清素 5HT2C 激动剂药物

• 批准号: 8029498
• 负责人: Raymond G. Booth
• 金额: $ 32.5万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-08 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8029498
• 关键词: Active Sites; Address; Adult; Affinity; Agonist; Amino Acids; Amphetamines; Animals; Behavior; Binding; Body Weight decreased; Brain; Cardiac; Cardiovascular Diseases; Cattle; Cells; Chemicals; Child; Data; Development; Diabetes Mellitus; Disease; Docking; Drug Evaluation; Eating; Electronics; Electrostatics; Evaluation; G-Protein-Coupled Receptors; Health; Homology Modeling; Human; In Vitro; Inhibitory Concentration 50; Inositol Phosphates; Knock-out; Lead; Ligands; Locomotion; Malignant Neoplasms; Maps; Membrane; Mental Depression; Mental disorders; Modeling; Molecular; Molecular Conformation; Molecular Mechanisms of Action; Molecular Models; Morbidity - disease rate; Mus; Mutagenesis; Mutate; Mutation; Obesity; Outcome; Overweight; Peripheral; Pharmaceutical Preparations; Pharmacotherapy; Phospholipase C; Point Mutation; Positioning Attribute; Psychotic Disorders; Pulmonary Hypertension; Quantitative Structure-Activity Relationship; Receptor Signaling; Recombinants; Relative (related person); Reporting; Research; Role; Serotonin; Structure; Study models; Testing; aged; analog; attenuation; base; cardiovascular disorder risk; chemical synthesis; computational chemistry; drug structure; drug testing; food consumption; in vivo; innovation; molecular modeling; molecular recognition; neurobehavioral; neuropsychiatry; pharmacophore; pre-clinical; preclinical evaluation; preclinical study; psychologic; receptor; receptor binding; rho; social; tetralin; three dimensional structure

DESCRIPTION (provided by applicant): There is compelling evidence that activation of brain serotonin 5HT2C G protein-coupled receptors (GPCRs) produces anti-obesity effects in humans, attenuation of psychomimetic activity, and other neuropsychiatric effects. Meanwhile, activation of brain 5HT2A GPCRs produces psychomimetic effects and activation of peripheral 5HT2B GPCRs produces cardiac valvulopathy and pulmonary hypertension. Currently, there is no 5HT2C receptor agonist reported that does not also activate 5HT2A and/or 5HT2B receptors. This research proposes to exploit a compound synthesized in our lab, (1R,3S)-(-)-trans-1-phenyl-3-dimethylamino-1,2,3,4- tetrahydronaphthalene (PAT), that is a full-efficacy agonist at human 5HT2C receptors, plus, it is an antagonist at 5HT2A and 5HT2B receptors. As a small (MW=250) lipophilic molecule, (-)-trans-PAT readily penetrates mouse brain after peripheral (IP) administration to inhibit food consumption, produce weight loss, and inhibit amphetamine-induced locomotion, neurobehavioral effects consistent with 5HT2C agonism and 5HT2A antagonism. This research proposes preclinical evaluation of (-)-trans-PAT as pharmacotherapy for obesity and neuropsychiatric disorders, and, synthesis of other PATs with potent and efficacious 5HT2C agonist activity; PATs with potent 5HT2A/5HT2B antagonism may be lead drugs for psychiatric or cardiovascular diseases. We also have identified a potent PAT-type 5HT2C inverse agonist useful especially to characterize molecular determinants involved in ligand-directed 5HT2C function. Targeted medicinal chemical syntheses will provide PAT type stereo-probes as test drugs for preclincial evaluation and to map molecular determinants for 5HT2C binding/activation for inferences of receptor 3D structure. Forty PATs already are available and 32 new analogs will help delineate the PAT- 5HT2C pharmacophore - the optimal PAT steric, lipophilic, and electronic chemical molecular features. In vitro binding/functional studies will continue to be conducted using clonal cells expressing recombinant human 5HT2A, 5HT2B, or 5HT2C receptors - preliminary results and PAT-5HT2C 3D QSAR and receptor homology models lead us to propose construction and expression of D3.32A, S3.36A, A5.46N, A5.46S, F5.47A, F5.48A, W6.48A, F6.51A, F6.52A, Y7.43A, & Y7.53A point-mutated 5HT2C receptors to validate hypothesized PAT- 5HT2C binding/function interactions. In an iterative fashion, pharmacological results and molecular models generate additional hypotheses to test involving additional PAT syntheses and 5HT2C point-mutations for receptor characterization and development of PAT-type 5HT2C agonist drug structures. Preclinical studies to evaluate PATs as pharmacotherapy for obesity, eating and other neuropsychiatric disorders, as well as, to determine in vivo molecular mechanisms of action, are conducted using wild-type vs. genetically modified mice with global disruption ("knock-out") of 5HT2C and 5HT2A receptor signaling. PUBLIC HEALTH RELEVANCE: About 65% of adults and 16% of children aged 6-19 years in the U.S. currently (2005) are overweight or obese. Obesity is associated with increased risk for cardiovascular disease; diabetes; certain forms of cancer, depression, and various other physical, psychological, and social morbidities. Current pharmacotherapy available for obesity is unsatisfactory. This research seeks to develop new drugs to treat obesity, as well as, certain neuropsychiatric disorders.

描述（由申请人提供）：有令人信服的证据表明，脑血清素5HT2C G蛋白偶联受体（GPCR）的激活会对人类产生抗肥胖作用，心理活性的衰减以及其他神经精神上的影响。同时，脑5HT2A GPCR的激活产生心理效应，外围5HT2B GPCR的激活产生心脏瓣膜病和肺动脉高压。目前，没有5HT2C受体激动剂报道也没有激活5HT2A和/或5HT2B受体。这项研究建议利用实验室中合成的化合物（1R，3s） - （ - ） - trans-1-苯基-3-二甲基氨基-1,2,3,3,4-四氢萘（PAT），它是人类5HT2C受体的全效率激动剂，此外，它是人类5HT2C受体的全效性激动剂，此外，它是一个抗抗抗剂和5ht2a的受体和5htt2a。作为一个小（MW = 250）的亲脂性分子，（ - ） - Trans-PAT在外周（IP）给药后很容易穿透小鼠大脑，以抑制食物消耗，产生体重减轻并抑制苯丙胺诱导的运动，神经行为，神经行为效应，与5HT2C Agonism和5ht2c agonism和5ht2c Antt2a Antagon Antagonims一致。这项研究提出了（ - ） - trans-pat作为肥胖和神经精神疾病的药物疗法的临床前评估，并综合具有有效和有效的5HT2C激动剂活动的其他PATS；具有有效5HT2A/5HT2B拮抗作用的PATS可能是精神病或心血管疾病的铅药物。我们还确定了有效的PAT型5HT2C反激动剂，特别是表征参与配体指导5HT2C功能的分子决定因素。有针对性的药物化学合成将提供PAT类型的立体探针作为测试药物，用于脱落评估，并绘制5HT2C结合/激活受体3D结构的5HT2C结合/激活的分子决定因素。已经有40张轻拍了，32个新的类似物将有助于描绘PAT -5HT2C药片 - 最佳的PAT定位，亲脂性和电子化学分子特征。 In vitro binding/functional studies will continue to be conducted using clonal cells expressing recombinant human 5HT2A, 5HT2B, or 5HT2C receptors - preliminary results and PAT-5HT2C 3D QSAR and receptor homology models lead us to propose construction and expression of D3.32A, S3.36A, A5.46N, A5.46S, F5.47A, F5.48A, W6.48A，F6.51A，F6.52A，Y7.43A和Y7.53A点突变的5HT2C受体，以验证假设的PAT-5HT2C结合/功能相互作用。以迭代方式，药理学结果和分子模型产生了其他假设，以测试涉及其他PAT合成和5HT2C点突变，以进行受体表征和开发Pat-Type 5HT2C激动剂药物结构。临床前研究将PAT评估为肥胖，饮食和其他神经精神疾病的药物疗法，以及确定体内分子作用机制，使用野生型与5HT2C和5HT2C和5HT2A受体的遗传修饰的小鼠进行野生型与遗传修饰的小鼠进行。公共卫生相关性：目前（2005年）在美国（2005年）的6-19岁儿童中，约有65％的成年人和16％的儿童超重或肥胖。肥胖与心血管疾病的风险增加有关；糖尿病;某些形式的癌症，抑郁症以及其他各种身体，心理和社会病性。当前可用于肥胖症的药物治疗不令人满意。这项研究旨在开发新药来治疗肥胖症以及某些神经精神疾病。