SBIR Triple Re-Uptake Inhibitors: Potential Antidepressants

描述（由研究者提供）：这是一个I期小型企业技术转让（STTR）资助申请，以响应精神疾病药物和药物（STTR [R41/R42]）。这项为期1年的提案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）、5-羟色胺（SERT）和多巴胺（DAT）的转运蛋白。来自临床文献的有力证据表明，阻断去甲肾上腺素和5-羟色胺再摄取的抗抑郁药的缓解率更高。虽然低多巴胺与抑郁症的病理生理学有关，特别是快感缺乏的特征，但目前还没有有效阻断所有3种转运蛋白的抗抑郁药。一种阻断所有3种转运蛋白的药物很可能是一种非常有效的，而且可能是一种起效更快的抗抑郁药。这项工作是可能的，我们的抗抑郁药文拉法辛类似物的合成。与文拉法辛不同，我们的化合物是三重再摄取抑制剂。将对3对对映异构体进行拟定的临床前研究，我们已将其从称为PRC 006、PRC 011和PRC 012的外消旋化合物中分离出来。所有这些外消旋混合物在预测抗抑郁活性的临床前试验中是有活性的。这些化合物已被授予美国专利，主要研究者（E。Richelson）和顾问（P. Carlier）在共同发明人（美国专利#6，069，177，2000年5月30日）中提出了该授权申请。本授权申请的具体目的是合成200 mg的每种化合物，然后在体外测试每种化合物（在细胞系中表达的去甲肾上腺素、血清素和多巴胺的人转运蛋白上的结合活性;在人心脏离子通道（称为hERG）上的抑制活性，其有效活性将阻止进一步的发展;和对参与药物代谢的细胞色素P450酶的抑制活性。有了这些数据，我们将能够接受或拒绝下一个特定目标的化合物，这是预测人类抗抑郁作用的临床前测试。此外，由于DAT转运蛋白阻断剂具有一定的滥用倾向，对于最后一个特定目的，我们计划在与滥用倾向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）行为致敏; 2）停止重复治疗的戒断体征;和3）操作性条件反射范例中的强化，在实验室动物中训练按下杠杆以自我输注药物。将选择最有效的化合物（基于体外和体内数据）进行临床前毒理学试验。

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.