Trace Amine Receptor as Medication Development Targets

描述（由申请人提供）：已经鉴定了一个新的哺乳动物G蛋白偶联受体家族，可在几个脑区检测到。这类受体的一个成员，人TA1受体，已被发现结合内源性脑胺，存在少量（痕量胺），目前还没有具体的作用模式。结合激活腺苷酸环化酶，促进cAMP的产生，表明微量胺可能作为神经递质。除了结合内源性微量胺外，还发现TA1的大鼠直系同源物结合与药物滥用相关的试剂。具体来说，发现摇头丸、蓝冰（安非他明）和LSD（麦角林）等化合物可有效刺激大鼠TA1促进cAMP积累。如果人类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起作用。该提案的目标是提供开发药物所需的工具，以消除这些药物的影响。这需要理解结构变异对人TA受体活化和选择性的影响。因此，将系统评价一组具有已知行为效应的滥用药物对人TA1受体的效力和疗效，并使用适当的计算化学工具分析结果。这些结果将指导设计用于确定与人TA1受体的效力和功效相关的分子特征的合成程序。对其他神经调节系统中活性化合物的评价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.