Trace Amine Receptor as Medication Development Targets

描述（由申请人提供）：一个新的哺乳动物G蛋白偶联受体家族，在几个大脑区域可检测到，已被确定。这一类的一个成员，人类TA1受体，已经被发现与内源性脑胺结合，存在于少量（微量胺），其具体的作用方式目前还不清楚。这种结合激活腺苷酸环化酶，促进cAMP的产生，提示微量胺可能作为神经递质。除了结合内源性微量胺外，已经发现TA1的大鼠同源物可以结合与药物滥用有关的药物。具体来说，像摇头丸、蓝冰（安非他明）和LSD（麦角碱）这样的化合物被发现能有效地刺激大鼠TA1促进cAMP的积累。如果人类的TA1受体也是如此，这可能表明这些受体在这些化合物的致幻活性和成瘾过程中都有作用。这项建议的目标是提供必要的工具来开发药物，以抵消这些药物的影响。这需要了解结构变异对人类TA受体激活和选择性的影响。因此，我们将系统地评估一组已知具有行为效应的滥用药物对人类TA1受体的效力和功效，并利用适当的计算化学工具对结果进行分析。这些结果将指导一个合成程序的设计，以确定与人类TA1受体的效力和功效相关的分子特征。评估其他神经调节系统中的活性化合物将有助于确定选择性，这是药物开发中的一个重要考虑因素。

DESCRIPTION (provided by applicant): A new family of mammalian G protein-coupled receptors, detectable in several brain regions, has been identified. A member of this class, the human TA1 receptor, has been found to bind endogenous brain amines, present in small amounts (trace amines), for which no specific mode of action is currently known. The binding activates adenylyl cyclase to promote the production of cAMP, suggesting that the trace amines may act as neurotransmitters. In addition to binding endogenous trace amines, it has been found that the rat ortholog of TA1 binds agents associated with drug abuse. Specifically, compounds like ecstasy, and blue ice (amphetamines) and LSD (ergolines) were found to potently stimulate rat TA1 promoted cAMP accumulation. If the same holds true for the human TA1 receptor it may suggest that these receptors have a role in both the hallucinogenic activity of these compounds and in the addiction process. The goal of this proposal is to provide the tools necessary for development of medications to countermand the effects of these drugs. This requires an understanding of the effect of structural variation(s) on human TA receptor activation and on selectivity. Therefore, a group of drugs of abuse with known behavioral effects will be systematically evaluated for their potency and efficacy at human TA1 receptors and the results will be analyzed with appropriate computational chemistry tools. The results will guide a synthesis program designed to determine the molecular characteristics associated with potency and efficacy at the human TA1 receptor. Evaluation of active compounds in other neuromodulatory systems will assist in the determination of selectivity, an important consideration in medication development.