Novel selective alpha4beta2 nicotinic receptor antagonists for smoking cessation

 描述(申请人提供)：吸烟仍然是美国头号可避免的死亡原因，每年给经济造成数百亿美元的损失。目前的治疗方法包括用贴片或口香糖替代尼古丁，用安非他酮抑制多巴胺系统，用伐伦克林部分激活42神经元烟碱乙酰胆碱受体(NAChR)。所有这些药物在最初使用时都不是特别有效，即使在最初成功的情况下，无论治疗药物或疗法如何，复发率都接近80%。临床试验中的其他治疗方法包括非选择性nAChR拮抗剂甲乙胺、尼古丁抗体和行为矫正。与香烟成瘾性质关系最密切的nAChR是42nAChR。THi受体的激活被认为是尼古丁奖赏的主要中介，选择性但低亲和力的42nAChR拮抗剂DHE已被证明能阻断啮齿动物模型中尼古丁的自我给药。然而，很少有高亲和力和选择性的-4--2拮抗剂可用于戒烟药物的研究。从一个包含500多万个单独化合物的小分子组合文库开始，我们已经鉴定了选择性的nAChR化合物。在我们第一阶段应用的资助下，我们已经在42nAChR上鉴定出具有非常高的亲和力、效力和选择性的先导化合物，无论是结合亲和力还是体外功能活性。这两个化合物都是-4--2nAChRs的完全拮抗剂。一种化合物已被证明可以减弱尼古丁在大鼠体内的自我给药和恢复。在这个第二阶段的SBIR中，我们建议优化我们的先导化合物，以进一步改善类似药物的性能，同时保持或提高亲和力和选择性。在具体目标1中，类似于传统的药物发现“点击到铅”过程，将进行额外的SAR，以改善我们目前先导化合物的PK/PD性能。这一目标将包括药物化学，并结合体外亲和力和有效性测试以及药理学图谱来鉴定类药物化合物。特殊目标2将类似于药物发现中的“引导开发”过程，即选定的高亲和力和选择性拮抗剂将在一系列体外和体内测试中进行测试，以确定口服生物利用度、稳定性、血脑屏障穿透、药代动力学和HERG抑制。除了确定阻止大鼠体内尼古丁自我给药和恢复尼古丁的能力的体内有效性外，这一目标还将包括确定对运动、焦虑、抑郁和奖赏/厌恶的额外药理作用，以便选择化合物来推进未来的IND毒理学。

 DESCRIPTION (provided by applicant): Smoking remains the number one avoidable cause of death in the United States and costs the economy tens of billions of dollars every year. Current therapies include nicotine replacement with a patch or gum, inhibition of the dopamine system with bupropion, and partial activation of the 42 neuronal nicotinic acetylcholine receptor (nAChR) with varenicline. None of these have been particularly effective upon initial use, and even in the cases of initial success relapse rates are nearly 80% regardless of the treatment drugs or therapies. Additional therapies in clinical trials include the non-selective nAChR antagonist mecamylamine, nicotine antibodies, and behavior modification. The nAChR most closely associated with the addictive nature of cigarettes is the 42 nAChR. Activation of thi receptor is considered to be the primary mediator of nicotine reward and the selective but low affinity 42 nAChR antagonist DHE has been demonstrated to block nicotine self-administration in rodent models. However, there are very few high affinity and selective 42 antagonists available to examine as smoking cessation medications. Starting from a small molecule combinatorial library containing more than 5 million individual compounds, we have identified selective nAChR compounds. With funding from our Phase I application we have identified lead compounds with very high affinity, potency and selectivity, both with respect to binding affinity and in vitro functional activity, at the 42 nAChR. Both of these compounds ae full antagonists at 42 nAChRs. One compound has been demonstrated to attenuate nicotine self-administration and reinstatement in rats. In this Phase II SBIR, we propose to optimize our lead compounds to further improve drug-like properties, while maintaining or improving affinity and selectivity. In Specific Aim 1, similar to a traditional drug discovery "hit-to-lead" process, additional SAR will be conducted to improve the PK/PD properties of our current lead compounds. This aim will include medicinal chemistry and coupled with in vitro affinity and efficacy testing along with the pharmacological profiling to identify drug-like compounds. Specific Aim 2 will be similar to the "lead to development" process within drug discovery, in which selected high affinity and selective antagonists will be tested in a battery of in vitro and n vivo assays to determine oral bioavailability, stability, blood brain barrier penetration, pharmacokinetics, and hERG inhibition. In addition to determining in vivo efficacy for ability to block nicotine self-administration and reinstatement in rats, this aim will include the determination of additional pharmacological effects on locomotion, anxiety, depression, and reward/aversion, in order to choose compounds to move forward to future IND-enabling toxicology.