Trace Amine Receptor as Medication Development Targets

痕量胺受体作为药物开发目标

• 批准号: 7250224
• 负责人: ANITA H LEWIN
• 金额: $ 44.5万
• 依托单位: RESEARCH TRIANGLE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7250224
• 关键词: Adenylate Cyclase; Affect; Affinity; Agonist; Amines; Amphetamines; Amygdaloid structure; Behavioral; Binding; Biological; Bipolar Disorder; Brain; Brain region; Central Nervous System Diseases; Characteristics; Class; Condition; Cyclic AMP; Data; Descriptor; Development; Disease; Drug abuse; Electrostatics; Ergoline; Ergolines; Ergot Alkaloids; Evaluation; Family; G-Protein-Coupled Receptors; Goals; Human; Ice; Image; Mental Depression; Messenger RNA; Methods; Molecular; Moods; Mus; Neurotransmitters; Orthologous Gene; Pharmaceutical Preparations; Phenethylamine; Phenethylamines; Phylogenetic Analysis; Process; Production; Quantitative Structure-Activity Relationship; Rattus; Receptor Activation; Role; Screening procedure; Serotonin; System; TA1 amine receptor; Tars; Trees; Tryptamines; Tyramine; Variant; addiction; analog; computational chemistry; design; dipole moment; drug of abuse; ecstasy; frontier; functional outcomes; indexing; member; molecular orbital; mood regulation; octopamine receptor; partial response; pharmacophore; programs; receptor; receptor binding; response; size; tool; trend; tryptamine

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.

描述（由申请人提供）：已鉴定出哺乳动物 G 蛋白偶联受体的新家族，可在多个大脑区域中检测到。人类 TA1 受体是此类受体的一个成员，被发现可以结合少量存在的内源性脑胺（微量胺），目前尚不清楚其具体作用模式。这种结合激活腺苷酸环化酶，促进 cAMP 的产生，表明微量胺可能充当神经递质。除了结合内源性微量胺外，还发现 TA1 的大鼠直系同源物还结合与药物滥用相关的物质。具体来说，像摇头丸、蓝冰（安非他明）和LSD（麦角林）这样的化合物被发现可以有效刺激大鼠TA1促进cAMP的积累。如果人类 TA1 受体也是如此，则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发挥作用。该提案的目标是提供药物开发所需的工具，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，将系统地评估一组具有已知行为影响的滥用药物对人类 TA1 受体的效力和功效，并使用适当的计算化学工具对结果进行分析。结果将指导一个合成程序，该程序旨在确定与人类 TA1 受体的效力和功效相关的分子特征。对其他神经调节系统中活性化合物的评估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。