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，脑5-羟色胺5 HT 2C G蛋白偶联受体（GPCR）的激活可在人体中产生抗肥胖作用、减弱拟精神活动和其他神经精神作用。同时，脑5 HT 2A GPCR的激活产生拟精神效应，外周5 HT 2B GPCR的激活产生心脏瓣膜病和肺动脉高压。目前，没有报道不激活5 HT 2A和/或5 HT 2B受体的5 HT 2C受体激动剂。本研究拟开发本实验室合成的一种化合物（1 R，3S）-（-）-trans-1-phenyl-3-dimethylamino-1，2，3，4- tetrahydronaphthalene（PAT），该化合物是人5 HT_（2C）受体的全效激动剂，同时也是5 HT_（2A）和5 HT_（2B）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）给药后容易穿透小鼠脑，以抑制摄食，产生体重减轻，并抑制苯丙胺诱导的运动，神经行为效应与5 HT 2C激动和5 HT 2A拮抗作用一致。本研究提出了（-）-trans-PAT作为肥胖和神经精神疾病药物治疗的临床前评价，以及具有强效和有效的5 HT 2C激动剂活性的其他PAT的合成;具有强效5 HT 2A/5 HT 2B拮抗作用的PAT可能是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5 HT 2C反向激动剂，特别适用于表征参与配体导向的5 HT 2C功能的分子决定簇。靶向药物化学合成将提供PAT型立体探针作为临床前评价的试验药物，并绘制5 HT 2C结合/激活的分子决定簇，以推断受体3D结构。已经有40种PAT可用，32种新的类似物将有助于描述PAT-5 HT 2C药效团-最佳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5 HT 2A、5 HT 2B或5 HT 2C受体的克隆细胞进行体外结合/功能研究-初步结果和PAT-5 HT 2C 3D QSAR和受体同源性模型使我们提出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5 HT 2C受体以验证假设的PAT-5 HT 2C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额外的假设，以测试涉及额外的PAT合成和5 HT 2C点突变的受体表征和PAT型5 HT 2C激动剂药物结构的开发。评价PAT作为肥胖症、进食和其他神经精神障碍的药物疗法以及确定体内分子作用机制的临床前研究使用具有5 HT 2C和5 HT 2A受体信号传导的整体破坏（“敲除”）的野生型小鼠与遗传修饰的小鼠进行。公共卫生相关性：目前（2005年），美国6-19岁的成年人和儿童中约有65%超重或肥胖。肥胖与心血管疾病、糖尿病、某些形式的癌症、抑郁症和各种其他身体、心理和社会疾病的风险增加有关。目前可用于肥胖症的药物治疗是不令人满意的。这项研究旨在开发新的药物来治疗肥胖症，以及某些神经精神疾病。

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.