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

描述(由申请人提供)：有令人信服的证据表明，大脑5-羟色胺5HT2C G蛋白偶联受体(GPCRs)的激活可以产生人类的抗肥胖效果、拟精神活动的减弱以及其他神经精神效应。同时，脑内5HT2a GPCRs的激活产生拟心理效应，外周5HT2b GPCRs的激活产生心脏瓣膜病和肺动脉高压。目前，还没有报道5HT2C受体激动剂也不能激活5HT2a和/或5HT2b受体。本研究拟开发本实验室合成的化合物(1R，3S)-(-)-trans-1-phenyl-3-dimethylamino-1，2，3，4-四氢萘(PAT)，它是人5HT2C受体的全效激动剂，同时也是5HT2a和5HT2b受体的拮抗剂。作为一种小分子(分子量为250)的亲脂分子，(-)-反式PAT在外周(Ip)给药后很容易渗透到小鼠脑内，从而抑制食物消耗、体重减轻和苯丙胺诱导的运动，神经行为效应与5HT2C激动剂和5HT2A拮抗剂一致。本研究建议对(-)-反式-PAT作为治疗肥胖和神经精神疾病的药物治疗进行临床前评估，并合成其他具有有效的5HT2C激动剂活性的PATS；具有有效的5HT2a/5HT2b拮抗作用的PATS可能是治疗精神或心血管疾病的主要药物。我们还发现了一种有效的PAT型5HT2C反向激动剂，特别适用于研究参与配体导向的5HT2C功能的分子决定因素。靶向药物化学合成将提供PAT类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图，以推断受体的3D结构。40个PATs已经上市，32个新的类似物将帮助描绘PAT-5HT2C药效团-最佳的PAT空间、亲脂和电子化学分子特征。体外结合/功能研究将继续使用表达重组人5HT2A、5HT2b或5HT2C受体的克隆细胞-初步结果和PAT-5HT2C 3D QSAR和受体同源模型导致我们建议构建和表达D3.32A、S3.36A、A5.46N、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。以迭代的方式，药理学结果和分子模型产生了额外的假设来测试，涉及额外的PAT合成和5HT2C点突变，用于受体表征和开发PAT型5HT2C激动剂药物结构。评估PATS作为治疗肥胖、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的临床前研究是使用5HT2C和5HT2A受体信号的全球干扰(“敲除”)野生型和转基因小鼠进行的。与公共卫生相关：美国目前(2005年)约65%的6-19岁成年人和16%的儿童超重或肥胖。肥胖与心血管疾病、糖尿病、某些形式的癌症、抑郁症以及其他各种生理、心理和社会疾病的风险增加有关。目前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症以及某些神经精神障碍的新药。

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.