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: 7609006
• 负责人: Raymond G. Booth
• 金额: $ 40.31万
• 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/7609006
• 关键词: Active Sites; Address; Adult; Affinity; Age; 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; Homology Modeling; Human; In Vitro; Inhibitory Concentration 50; Inositol Phosphates; Knock-out; Lead; Ligands; Locomotion; Malignant Neoplasms; Maps; Membrane; 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; Tetrahydronaphthalenes; analog; attenuation; base; cardiovascular disorder risk; chemical synthesis; computational chemistry; depression; drug structure; drug testing; food consumption; in vivo; innovation; molecular modeling; molecular recognition; neurobehavioral; neuropsychiatry; pharmacophore; pre-clinical; preclinical evaluation; preclinical study; psychologic; public health relevance; receptor; receptor binding; rho; social; 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，大脑血清素 5HT2C G 蛋白偶联受体 (GPCR) 的激活可在人类中产生抗肥胖作用、减弱拟心理活性和其他神经精神作用。同时，大脑 5HT2A GPCR 的激活会产生拟心理作用，外周 5HT2B GPCR 的激活会产生心脏瓣膜病和肺动脉高压。目前，还没有报道不同时激活5HT2A和/或5HT2B受体的5HT2C受体激动剂。本研究计划开发我们实验室合成的化合物 (1R,3S)-(-)-trans-1-苯基-3-二甲基氨基-1,2,3,4-四氢萘 (PAT)，它是一种全人类 5HT2C 受体的功效激动剂，此外，它还是 5HT2A 和 5HT2B 受体的拮抗剂。作为一种小的 (MW=250) 亲脂性分子，(-)-trans-PAT 在外周 (IP) 给药后很容易渗透小鼠大脑，抑制食物消耗，产生体重减轻，并抑制安非他明诱导的运动，神经行为效应与 5HT2C 激动作用一致和5HT2A拮抗作用。这项研究建议对 (-)-trans-PAT 作为肥胖和神经精神疾病的药物疗法进行临床前评估，并合成具有强效和有效 5HT2C 激动剂活性的其他 PAT；具有强效 5HT2A/5HT2B 拮抗作用的 PAT 可能是治疗精神或心血管疾病的先导药物。我们还鉴定了一种有效的 PAT 型 5HT2C 反向激动剂，特别适用于表征配体导向的 5HT2C 功能中涉及的分子决定因素。靶向药物化学合成将提供 PAT 型立体探针作为临床前评估的测试药物，并绘制 5HT2C 结合/激活的分子决定因素，以推断受体 3D 结构。已有 40 种 PAT 可供使用，32 种新类似物将有助于描绘 PAT-5HT2C 药效团 - 最佳的 PAT 空间、亲脂性和电子化学分子特征。将继续使用表达重组人 5HT2A、5HT2B 或 5HT2C 受体的克隆细胞进行体外结合/功能研究 - 初步结果和 PAT-5HT2C 3D QSAR 和受体同源模型使我们建议构建和表达 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 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额外的假设来测试，涉及额外的 PAT 合成和 5HT2C 点突变，用于受体表征和 PAT 型 5HT2C 激动剂药物结构的开发。使用野生型小鼠与全局破坏（“敲除”）的转基因小鼠进行临床前研究，以评估 PAT 作为治疗肥胖、饮食和其他神经精神疾病的药物疗法，并确定体内分子作用机制。 5HT2C 和 5HT2A 受体信号传导。公共卫生相关性：目前（2005 年）美国约 65% 的成年人和 16% 的 6-19 岁儿童超重或肥胖。肥胖与心血管疾病风险增加有关；糖尿病;某些形式的癌症、抑郁症以及各种其他身体、心理和社会疾病。目前可用于治疗肥胖症的药物疗法并不令人满意。这项研究旨在开发治疗肥胖以及某些神经精神疾病的新药。