Chemistry and Biology of 5-HT2C Receptor Ligands for Drug 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、情绪、注意力和食欲等。此外，有大量数据表明，5-羟色胺参与介导精神运动兴奋剂的作用，如可卡因和MDMA或“摇头丸”。此外，越来越多的证据表明，大脑中的血清素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服药行为方面的调节作用。5-HT2受体家族是大脑中5-羟色胺作用的关键部位，最近的证据强烈表明5-HT2受体在控制药物服用行为中非常重要。迄今为止，寻找可卡因成瘾药物疗法的努力在很大程度上忽视了基于5-HT2R药理学的药物治疗前景。似乎5-HT2受体的功能包括对5-HT2AR的兴奋作用和对5-HT2CR的抑制作用，以控制一些明显的兴奋剂诱导的行为。此外，5-HT2AR和5-HT2CR可能在可卡因和环境刺激（“线索”）之间形成的强烈条件关联中发挥作用。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，瓣膜性心脏病与5-HT2B亚型的激活有关，幻觉是由5-HT2AR的激活引起的。基于化学文库的筛选，我们已经确定了丙基环丙氨酸作为我们寻找有用的5HT2CR配体的可能的主要候选者。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5HT2CR配体。这些初步的努力为目前的拨款提供了基础，其目的是确定5HT2CR配体，这些配体既可以用作研究工具，也可以用作治疗可卡因成瘾和可能的其他疾病（包括肥胖）的潜在疗法。我们将测试作为5-HT2CR激动剂（或5-HT2AR拮抗剂）的化合物将被证明有助于减少大鼠自我给药（SA）范式中的可卡因使用。这些目标形式化如下：在现有SAR的基础上，开展进一步的化学研究，以进一步提高结合亲和力和亚型选择性；2. 筛选新的配体，以确定它们的结合亲和力，如果有必要，则筛选它们在三个5HT2受体上的功能活性。3. 这些具有5-HT2CR激动剂或5-HT2AR拮抗剂活性的化合物将在大鼠身上进行评估，以评估在一系列越来越复杂的大鼠实验中的行为活性，这些实验将确定它们作为减少或预防可卡因滥用的有效药物的可行性。

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.