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: 7321298
• 负责人: ALAN Paul KOZIKOWSKI
• 金额: $ 50.78万
• 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/7321298
• 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）：血清素介导或调节多种行为，包括认知、情感、注意力和食欲等。此外，有大量数据表明，5-羟色胺参与介导可卡因和摇头丸或“摇头丸”等精神兴奋剂的作用。此外，越来越多的证据表明，大脑中的多巴胺能系统也调节多巴胺能奖励系统和其他因素，包括环境因素在维持药物服用行为中的调节作用。5-HT 2受体家族代表了大脑中5-羟色胺的关键作用部位，最近的证据强烈表明5-HT 2受体在控制药物服用行为方面非常重要。迄今为止，寻求确定可卡因成瘾的药物疗法在很大程度上忽视了基于5-HT 2 R药理学的药物的前景。似乎5-HT 2受体功能包括5-HT 2AR的兴奋作用和5-HT 2CR在控制某些明显的刺激诱导的行为中的抑制作用。此外，5-HT 2AR和5-HT 2CR可能在可卡因和环境刺激（“线索”）之间的强条件性关联中发挥作用。同样清楚的是，需要开发具有高选择性和特异性的药物，因为与几种相关（和不相关）受体的相互作用可能与显著的发病率和死亡率相关。例如，心脏瓣膜病与5-HT 2B亚型的激活有关，幻觉是由5-HT 2AR的激活引起的。基于筛选的化学库，我们已经确定反苯环丙胺作为一个可能的铅候选人，在我们寻求确定有用的5 HT 2CR配体。经过初步的SAR工作，我们已经确定了一些有效的和选择性的5 HT 2CR配体。这些初步的努力提供了本赠款的基础，其目的是确定5 HT 2CR配体，可用作研究工具和潜在的治疗药物，用于治疗可卡因成瘾和可能的其他疾病，包括肥胖症。我们将测试总体假设，即作为5-HT 2CR激动剂（或5-HT 2AR拮抗剂）的化合物将证明在减少大鼠自我给药（SA）范式中可卡因的使用是有用的。这些目标形式化如下：1.基于目前的SAR，进行额外的化学研究，目的是进一步增强结合亲和力和亚型选择性; 2.筛选新配体的结合亲和力，如果有必要，筛选其对三种5 HT 2受体的功能活性。3.将在大鼠中评价具有5-HT 2CR激动剂或5-HT 2AR拮抗剂活性的那些化合物，以在一系列复杂性增加的大鼠实验中评估行为活性，所述实验将确定它们作为可用于减少或预防可卡因滥用的药剂的可行性。