SBIR Triple Re-Uptake Inhibitors: Potential Antidepressants

描述（由研究者提供）：这是一项针对精神障碍药物制剂和药物（STTR [R41/R42]）的I期小企业技术转移（STTR）拨款申请。这项为期1年的研究的目标是确定一种具有新作用机制的潜在抗抑郁药。这种新的作用机制是阻断神经递质去甲肾上腺素（NET）、血清素（SERT）和多巴胺（DAT）的转运体。来自临床文献的令人信服的证据表明，使用阻断去甲肾上腺素和血清素再摄取的抗抑郁药，缓解率更高。虽然低多巴胺与抑郁症的病理生理有关，特别是快感缺乏的特征，但目前还没有抗抑郁药能有效阻断这三种转运蛋白。阻断这三种转运蛋白的药物很可能是一种非常有效的，而且可能是一种快速起效的抗抑郁药。这项工作是通过我们合成抗抑郁药文拉法辛的类似物而实现的。与文拉法辛不同，我们的化合物是三重再摄取抑制剂。我们将对3对对映体进行临床前研究，这些对映体是我们从外消旋化合物PRC006、PRC011和PRC012中分离出来的。所有这些外消旋混合物在临床前试验中都具有抗抑郁活性。这些化合物已经获得了美国专利，共同发明人中的首席研究员（E. Richelson）和顾问（P. Carlier）获得了这项授权申请（美国专利#6,069,177,2000年5月30日）。该资助申请的具体目标是合成每种化合物200毫克，然后在体外测试每种化合物(与人类转运蛋白结合的活性，在细胞系中表达的去甲肾上腺素、血清素和多巴胺；对人类心脏离子通道（称为hERG）的抑制活性，这种强效活性将阻止进一步的开发；以及对细胞色素P450酶的抑制活性，这与药物代谢有关。有了这些数据，我们将能够接受或拒绝一种化合物用于下一个特定目标，这是预测抗抑郁药对人类影响的临床前测试。此外，由于DAT转运蛋白阻断有滥用的风险，对于最后一个特异性Aim，我们计划在与滥用风险相关的临床前模型中测试我们选择的化合物。这些模型是：1)行为敏感化；2)停止重复治疗后出现戒断症状；3)在操作性条件反射范式中，实验动物被训练按下杠杆以自我注入药物。将选择最有效的化合物（基于体外和体内数据）进行临床前毒理学测试。

DESCRIPTION (provided by investigator):This is a Phase I Small Business Technology Transfer (STTR) grant application in response to Pharmacologic Agents and Drugs for Mental Disorders (STTR [R41/R42]). The goal of this proposal of 1 year's length is to identify a potential antidepressant with a novel mechanism of action. This novel mechanism of action is the blockade of transporters for the neurotransmitters norepinephrine (NET), serotonin (SERT), and dopamine (DAT). Compelling evidence from the clinical literature suggests that remission rates are higher with antidepressants that block re-uptake of both norepinephrine and serotonin. While low dopamine has been implicated in the pathophysiology of depression, particularly the feature of anhedonia, there is currently no antidepressant that potently blocks all 3 transporters. It is likely that a drug that blocks all 3 transporters would be a very efficacious and possibly, a faster-acting antidepressant. This work is made possible by our synthesis of analogs of the antidepressant venlafaxine. Unlike venlafaxine, our compounds are triple re-uptake inhibitors. The proposed preclinical studies will be done on 3 pairs of enantiomers, which we have resolved from the racemic compounds called PRC006, PRC011, and PRC012. All these racemic mixtures are active in preclinical tests predictive of antidepressant activity. A U.S. Patent has been issued on these compounds, with the Principal Investigator (E. Richelson) and Consultant (P. Carlier) of this grant application among the co-inventors (U.S. Patent #6,069,177, May 30, 2000). The Specific Aims of this grant application are to synthesize 200 mg of each compound and then test each in vitro (binding activity at human transporters for norepinephrine, serotonin, and dopamine expressed in cell lines; inhibitory activity at a human cardiac ion channel, called hERG, potent activity at which would preclude further development; and inhibitory activity at cytochrome P450 enzymes, which are involved in drug metabolism. With these data, we will be able to accept or reject a compound for the next Specific Aim, which is the preclinical tests predictive of antidepressant effects in humans. In addition, because DAT transporter blockade has some liability for abuse, for the last Specific Aim, we plan to test our selected compound in preclinical models that relate to abuse liability. These models are 1) behavioral sensitization; 2) withdrawal signs with cessation of repeated treatment; and 3) reinforcement in an operant-conditioning paradigm, in laboratory animals are trained to press a lever to self-infuse the drug. The most potent compound (based on the in vitro and in vivo data) will be chosen to take into preclinical toxicology testing.