Development of Potential Treatment Medications for Drug Abuse

描述（由申请人提供）：R01 DA12970竞争性修订的主要目的是评估5HT1a、5HT2a、5HT2b和5HT2c受体各种功能终点的化合物。目标有两个，(1)通过消除所有5HT1a、5HT2a和5HT2b活性，加速药物滥用治疗的安全药物的发现和开发；(2)识别这些受体的功能选择性化合物，作为确定哪些第二信使途径与特定行为或疗效终点相连的工具。本项目的初始目标是设计、合成和评估多巴胺（DA）、血清素（5-HT）和去甲肾上腺素（NE）释放剂。迄今为止，大多数对兴奋剂成瘾的“激动剂”治疗的努力都集中在选择性DA摄取阻断剂的发现上。然而，越来越多的证据表明，可能需要双DA/5-HT选择性或非选择性化合物来“纠正”戒断期间兴奋剂引起的全部缺陷。竞争性修订的一个项目目标是筛选5HT1a、5HT2a和5HT2b受体的化合物，以出于安全原因消除活性。5HT1a和5HT2a激动剂活性与致幻活性有关。5HT2b与肺瓣膜病有关。亲本赠款包含筛选这些受体，但仅使用受体诱导的钙动员作为激动剂活性的指标。新出现的证据表明，钙外排在这两种情况下都不完全相关，需要更广泛的功能终点来确保消除这种活性。化合物将在这三种受体的每一个额外的5个终点进行评估。消除活性将确保开发更安全的候选药物。在此过程中，每种受体的功能选择性激动剂也将被确定为研究功能选择性配体的工具。5HT2c受体也将包括在内，因为最近的证据表明，5HT2c激动剂活性可能对兴奋剂成瘾药物有用，特别是在复发时。

DESCRIPTION (provided by applicant): The primary objective of this competitive revision to R01 DA12970 is to assess compounds in a variety of functional endpoints of the 5HT1a, 5HT2a, 5HT2b and 5HT2c receptors. The goals are two-fold, (1) to speed up the discovery and development of safe medications for the treatment of substance abuse by eliminating all 5HT1a, 5HT2a, and 5HT2b activity from the releasers developed on the parent grant; and (2) to identify functionally selective compounds of these receptors to use as tools for determining which second messenger pathways are connected to specific behavioral or efficacy endpoints. The initial objective of the parent grant program is to design, synthesize, and evaluate dopamine (DA), serotonin (5-HT), and norepinephrine (NE) releasers. To date, most efforts towards an "agonist" therapy of stimulant addiction have concentrated on the discovery of selective DA uptake blockers. However increasing evidence shows that dual DA/5-HT selective or non-selective compounds may be required to "correct" the totality of stimulant-induced deficits during withdrawal. A project aim in the competitive revision is to screen compounds at 5HT1a, 5HT2a, and 5HT2b receptors to eliminate activity for safety reasons. 5HT1a and 5HT2a agonist activity has been linked to hallucinogenic activity. 5HT2b has been linked to pulmonary valvulopathy. The parent grant contains screening of these receptors, but only using receptor-induced calcium mobilization as the indicator of agonist activity. Emerging evidence suggests that calcium efflux does not completely correlate in either case, and that a wider array of functional endpoints is required to ensure elimination of this activity. Compounds will be assessed at 5 additional endpoints for each of the three receptors. Elimination of activity will ensure the development of safer drug candidates. In the process functionally selective agonists for each receptor will also be identified as tools for the study of functionally selective ligands. The 5HT2c receptor will also be included since recent evidence shows that 5HT2c agonist activity may be useful in a stimulant-addiction medication, especially in relapse. PUBLIC HEALTH RELEVANCE: Stimulant abuse and addiction continues to be a major societal problem the United States. Mounting evidence suggests that one of the best methods for combating stimulant addiction is the agonist approach in which drugs replace the biochemical deficits caused by chronic stimulant. Such an approach may be the only way to address the wide ranges of symptoms observed during withdrawal as well as the urge to relapse into drug taking behavior. Safe, dual dopamine/serotonin releasers represent one approach to such agonist therapies and will be developed in this research program.