Chemistry and Biology of 5-HT2C Receptor Ligands for Drug Abuse

药物滥用中 5-HT2C 受体配体的化学和生物学

• 批准号: 7501965
• 负责人: alan P. kozikowski
• 金额: $ 52.32万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7501965
• 关键词: Adverse effects; Affinity; Agonist; Anxiety; Attention; Behavior; Behavioral; Binding; Biological Assay; Biological Availability; Biology; Brain; Cells; Cessation of life; Chemistry; Cocaine; Cocaine Abuse; Cocaine Dependence; Cognition; Condition; Coronary Arteriosclerosis; Cues; Data; Databases; Desire for food; Disease; Dose; Drug Controls; Drug Design; Drug abuse; Drug usage; Eating Disorders; Emotions; Environmental Risk Factor; Family; Family member; Generations; Grant; Hallucinations; Hand; Heart Valve Diseases; Individual; Lead; Ligands; Mediating; Mental Depression; Modeling; Molecular Target; Morbidity - disease rate; Numbers; Obesity; Obsessive-Compulsive Disorder; Overweight; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Play; Prevention; Process; Range; Rattus; Reporting; Research; Rewards; Risk Factors; Role; Schizophrenia; Screening procedure; Second Messenger Systems; Self Administration; Series; Serotonin; Serotonin Receptor 5-HT2C; Site; Solid; Specificity; Stimulus; Structure; System; Testing; Therapeutic; Therapeutic Uses; Time; Tranylcypromine; Work; base; chronic pain; conditioning; design; drug development; ecstasy; in vivo; mortality; pharmacophore; programs; receptor; receptor function; research study; second messenger; serotonin receptor; small molecule libraries; tool

DESCRIPTION (provided by applicant): Serotonin mediates or regulates a wide variety of behaviors including cognition, emotion, attention, and appetite among others. In addition, there is substantial data suggesting that 5-HT is involved in mediating the effects of psychomotor stimulants such as cocaine and MDMA or "ecstasy". Further, there is increasing evidence that serotonergic systems in the brain also regulate dopaminergic reward systems and other factors including the conditioning effects that environmental factors have in maintaining drug taking behavior. The 5-HT2 family of receptors represent key sites of action of serotonin in the brain, and recent evidence strongly suggests that 5-HT2 receptors are very important in controlling drug taking behavior. To date, the quest to identify pharmacotherapies for cocaine addiction has largely overlooked the prospects of medications based upon 5-HT2R pharmacology. It appears that 5-HT2 receptor functions include an excitatory role for the 5-HT2AR and an inhibitory role for the 5-HT2CR in the control of some overt stimulant- induced behaviors. Furthermore, the 5-HT2AR and 5-HT2CR may play a role in the strong conditioned associations made between cocaine and environmental stimuli ("cues"). It is also clear that drugs with high selectivity and specificity will need to be developed because interaction with several related (and unrelated) receptors can be associated with significant morbidity and mortality. For example, valvular heart disease is associated with activation of the 5-HT2B subtype and hallucinations are caused by activation of the 5-HT2AR. Based upon screening of a chemical library, we have identified tranylcypromine as a possible lead candidate in our quest to identify useful 5HT2CR ligands. After preliminary SAR work, we have identified some potent and selective 5HT2CR ligands. These preliminary efforts provide the basis of the present grant whose aim is to identify 5HT2CR ligands that can be used both as research tools and as potential therapeutics for use in treating cocaine addiction and possibly other disorders, including obesity. We will test the overarching hypothesis that compounds that act as 5-HT2CR agonists (or 5-HT2AR antagonists) will prove useful in reducing cocaine use in rat self-administration (SA) paradigms. These aims are formalized as follow: 1. Based upon the SAR now in hand, carry out additional chemistry studies with the aim of further enhancing binding affinity as well as subtype selectivity; 2. Screen new ligands for their binding affinity and if warranted, for their functional activity at the three 5HT2 receptors. 3. Those compounds with activity as 5-HT2CR agonists or 5-HT2AR antagonists will be evaluated in rats to assess behavioral activity in a series of rat experiments of increasing complexity that will determine their viability as agents useful in the reduction or prevention of cocaine abuse.

描述（由申请人提供）：5-羟色胺介导或调节各种各样的行为，包括认知，情感，注意力和食欲。此外，还有大量数据表明5-HT参与了可卡因和MDMA或“摇头丸”等心理刺激剂的影响。此外，有越来越多的证据表明，大脑中的血清素能系统还调节多巴胺能奖励系统以及其他因素，包括环境因素在维持药物服用行为方面所具有的调节作用。 5-HT2受体家族代表了脑中5-羟色胺的关键作用部位，最近的证据强烈表明5-HT2受体在控制药物的行为中非常重要。迄今为止，确定可卡因成瘾的药物治疗的追求在很大程度上忽略了基于5-HT2R药理学的药物前景。似乎5-HT2受体功能包括5-HT2AR的兴奋性作用，以及5-HT2CR在控制某些明显刺激剂诱导的行为中的抑制作用。此外，5-HT2AR和5-HT2CR可能在可卡因和环境刺激之间建立的强度有条件的关联中发挥作用（“提示”）。同样很明显，需要高选择性和特异性的药物需要发展，因为与几种相关（和无关）受体的相互作用可能与显着的发病率和死亡率有关。例如，瓣膜心脏病与5-HT2B亚型的激活有关，幻觉是由5-HT2AR激活引起的。根据化学文库的筛选，我们确定了tranylcypromine是我们寻求识别有用的5HT2CR配体的可能的主要候选者。初步的SAR工作后，我们确定了一些有效和选择性的5HT2CR配体。这些初步的努力提供了当前赠款的基础，其目的是识别可用作研究工具的5HT2CR配体，也可以用作治疗可卡因成瘾以及可能其他疾病（包括肥胖）的潜在疗法。我们将测试总体假设，即用作5-HT2CR激动剂（或5-HT2AR拮抗剂）的化合物将被证明可用于减少可卡因在大鼠自我给药（SA）范式中的可卡因使用。这些目标是正式化的：1。基于现在的SAR，进行其他化学研究，以进一步增强结合亲和力以及亚型选择性； 2。筛选新的配体具有结合亲和力，如果有必要，则在三个5HT2受体上的功能活性。 3。将在大鼠中评估具有5-HT2CR激动剂或5-HT2AR拮抗剂的活性的化合物，以评估复杂性增加的一系列大鼠实验中的行为活性，这将确定其可生存能力，以确定其作为对可卡因滥用减少或预防可卡因滥用的试剂的生存能力。