Development of Novel Drugs for Smoking Cessation Pharmacotherapy

描述（由申请人提供）：这个SBIR I期项目的总体目标是从我们的新系列非常有效和高选择性的烟碱乙酰胆碱受体（nAChR）配体中确定至少两种合适的，有效的临床前候选药物，用于进一步转化开发成戒烟药物。该系列中高选择性的¿3¿4 nAChR拮抗剂化合物在体内低剂量显著阻断大鼠尼古丁自我给药，且对食物反应无影响，这有力地支持了我们的假设，即“¿3¿4 nAChR拮抗剂”是戒烟药物治疗中有希望的新药理机制。并支持拟议的临床前ADME评估和疗效研究，以从该系列中确定两种合适的临床前候选药物进行进一步开发。虽然有证据表明，使用药物治疗的戒烟成功率比不使用药物治疗的戒烟成功率高2-3倍，但目前的药物治疗方法极为有限。吸烟给我们的社会带来了巨大的健康和经济负担，尽管目前可用的几种戒烟药物疗效有限，而且出现了副作用，但迫切需要开发新的戒烟药物，特别是针对新的药理学目标，以减少吸烟对健康和死亡率的影响。虽然我们知道尼古丁的强化和成瘾作用是由于它对尼古丁乙酰胆碱受体的作用，但该领域的一个主要障碍是鉴定在尼古丁依赖的各个方面发挥作用的各种nAChR亚型，以及它们作为药物靶点的有效性。由于缺乏亚型选择性nAChR配体（可作为工具或开发为治疗方法），这种情况加剧了。最近的几项研究表明，nAChR的¿3¿4亚型在尼古丁依赖的几个方面都很重要。最近的遗传关联研究表明，编码¿3、¿5和¿4 nAChR亚基的CHRNA5/A3/B4基因簇的单核苷酸多态性（snp）与重度吸烟、无法戒烟和尼古丁敏感性增加的风险相关。此外，nAChR亚基已被证明是尼古丁戒断所必需的。我们的高选择性¿3¿4 nAChR拮抗剂在体内的良好疗效表明，¿3¿4拮抗剂可能是戒烟的一个有希望的目标，似乎与最近关于¿3¿4亚型作用的遗传研究一致。基于这些结果，我们在本申请中提出了一项临床前开发计划，以评估该化合物系列在体外ADME研究、体内生物利用度和血脑渗透试验（Aim 1）中，选择两种候选化合物在尼古丁自我给药和恢复（药物复发模型）的动物模型中进行全面疗效评估（Aim 2）。还提出了先导物优化以提高初始系列化合物的药物样适应性（Aim 3）。我们的特定目标被设计为这类有前途的化合物作为烟草依赖药物治疗的临床前开发的第一步。

DESCRIPTION (provided by applicant): The overall goal of this SBIR Phase I project is to identify at least two suitable, efficacious preclinical candidates from our novel series of very potent and highly selective ¿3¿4 nicotinic acetylcholine receptor (nAChR) ligands, for further translational development into smoking cessation medications. The promising in vivo efficacy of the highly selective ¿3¿4 nAChR antagonist compound from this series in significant blocking nicotine self-administration in rats, at low doses, with no effect on food responding, strongly supports our hypothesis that '¿3¿4 nAChR antagonism' is a promising new pharmacological mechanism for smoking cessation pharmacotherapy, and supports the proposed preclinical ADME assessment and efficacy studies to identify two suitable preclinical candidates from this series for further development. Although there is evidence that success rates for quitting smoking, are 2-3 times higher when pharmacotherapy is used than when no treatments are used, the repertoire of current pharmacotherapies is extremely limited. With the enormous health and economic burdens that smoking has on our society, and notwithstanding the limited efficacy and emerging side-effects of the few currently available smoking cessation medications, development of new medications for smoking cessation, particularly against new pharmacological targets, is a critical need, to decrease the impact of smoking on health and mortality. Although it is known that the reinforcing and addictive effects of nicotine are due to is actions on the nicotinic acetylcholine receptors, a major barrier in the field has been the identification of the various nAChR subtypes that play a role in the various aspects of nicotine dependence, and their validation as drug targets. This has been exacerbated by lack of subtype-selective nAChR ligands that can be used as tools or developed as therapeutics. Several recent studies suggest that the ¿3¿4 subtype of the nAChR is important for several aspects of nicotine dependence. Recent genetic association studies show that single nucleotide polymorphisms (SNPs) in the gene cluster CHRNA5/A3/B4, encoding for the ¿3, ¿5 and ¿4 nAChR subunits are associated with increased risk for heavy smoking, inability to quit, and increased sensitivity to nicotine. Furthermore, the ¿4 nAChR subunit has been shown to be necessary for nicotine withdrawal. The promising in vivo efficacy of our highly selective ¿3¿4 nAChR antagonist suggests that ¿3¿4 antagonism may be a promising target for smoking cessation and appears to be consistent with the recent genetic studies on the role of the ¿3¿4 subtype. Based on these results, we propose, in this application, a preclinical development program to evaluate this compound series in in vitro ADME studies and in vivo biovailability and blood-brain penetration assays (Aim 1), to select two candidate compounds for full efficacy evaluation in animal models of nicotine self-administration and reinstatement (a model of drug relapse) (Aim 2). Lead optimization to improve the drug-like suitability of the initial series of compounds is also proposed (Aim 3). Our Specific Aims are designed as a first step toward the preclinical development of this promising class of compounds as pharmacotherapies for tobacco dependence. PUBLIC HEALTH RELEVANCE: The overall goal of the proposed research is to develop our novel ¿3¿4 nAChR antagonists as smoking cessation medications against a new target, the ¿3¿4 nAChRs, which have been recently implicated in several genetic studies, to be involved in smoking behaviors and withdrawal. Our exciting preliminary data shows that our lead compound dramatically inhibits nicotine self-administration in laboratory animal models. It is our ultimate goal to take this promising series of compounds into the clinic, and to provide a new, safe therapeutic option to assist smokers who wish to quit. Successful completion of this project will be the first step in this clinical translation of our promising discoveries, for the development of pharmacotherapies for smoking cessation.