Novel selective alpha4beta2 nicotinic receptor antagonists for smoking cessation

用于戒烟的新型选择性α4β2烟碱受体拮抗剂

• 批准号: 8779197
• 负责人: Jinhua Wu
• 金额: $ 15万
• 依托单位: ASSUAGE PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2015-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8779197
• 关键词: Absenteeism at work; Adverse effects; Affinity; Agonist; Attention; Attenuated; Binding; Biological Assay; Biological Availability; Blood - brain barrier anatomy; Brain; Bupropion; CH3OCF2CH(CF3)OCH2F; Cause of Death; Cells; Cessation of life; Chantix; Cigarette; Drug Kinetics; Exhibits; Future; Genetic; Goals; Grant; Hospitalization; In Vitro; Individual; Lead; Libraries; Ligands; Link; Measures; Mediator of activation protein; Membrane; Membrane Potentials; Methods; Modeling; Molecular Models; Nature; Neurons; Nicotine; Nicotine Dependence; Nicotinic Receptors; Patients; Penetration; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; Positioning Attribute; Preparation; Property; Rattus; Receptor Activation; Relapse; Rewards; Rodent Model; Scanning; Self Administration; Small Business Innovation Research Grant; Smoking; Structure; Techniques; Testing; Tobacco smoke; United States; addiction; analog; base; combinatorial; design; dopamine system; drug efficacy; epibatidine; improved; in vivo; molecular modeling; nicotine replacement; nicotinic receptor alpha4beta2; novel; public health relevance; receptor; research study; scaffold; screening; small molecule; smoking cessation; success; varenicline; Absenteeism at work; Adverse effects; Affinity; Agonist; Attention; Attenuated; Binding; Biological Assay; Biological Availability; Blood - brain barrier anatomy; Brain; Bupropion; CH3OCF2CH(CF3)OCH2F; Cause of Death; Cells; Cessation of life; Chantix; Cigarette; Drug Kinetics; Exhibits; Future; Genetic; Goals; Grant; Hospitalization; In Vitro; Individual; Lead; Libraries; Ligands; Link; Measures; Mediator of activation protein; Membrane; Membrane Potentials; Methods; Modeling; Molecular Models; Nature; Neurons; Nicotine; Nicotine Dependence; Nicotinic Receptors; Patients; Penetration; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; Positioning Attribute; Preparation; Property; Rattus; Receptor Activation; Relapse; Rewards; Rodent Model; Scanning; Self Administration; Small Business Innovation Research Grant; Smoking; Structure; Techniques; Testing; Tobacco smoke; United States; addiction; analog; base; combinatorial; design; dopamine system; drug efficacy; epibatidine; improved; in vivo; molecular modeling; nicotine replacement; nicotinic receptor alpha4beta2; novel; public health relevance; receptor; research study; scaffold; screening; small molecule; smoking cessation; success; varenicline

DESCRIPTION (provided by applicant): Smoking remains the number one avoidable cause of death in the United States. Current therapies including nicotine replacement, inhibition of the dopamine system with bupropion, and partial activation of the 4 2 neuronal nicotinic acetylcholine receptor (nAChR) with varenicline have not been particularly effective, with relapse rates at nearly 80% regardless of the treatment drugs or therapies. Furthermore, varenicline, the most efficacious drug, has serious psychiatric side effects. Clearly new treatments are needed. The nAChR most closely associated with the addictive nature of cigarettes is the 4 2 nAChR. Activation of this receptor is 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. Currently there are no high affinity and selective 4 2 antagonists available to examine as smoking cessation medications. Starting from a small molecule combinatorial library containing over 5 million individual compounds, we have identified selective 4 2 nAChR compounds. Using these screening hits along with medicinal chemistry and molecular modeling, we have identified two lead compounds (2187.397 and 2187.202), one with very high affinity (37 nM) and moderate selectivity (23 fold) in binding assays, and a second with excellent selectivity (>500 fold) but slightly lower affinity (114nM) at the 4 2 nAChR. Both of these compounds are antagonists at 4 2 nAChRs with remarkable in vitro selectivity. In vitro functional assays showed that 202 has 400 fold selectivity at 4 2 over 3 4 nAChR. Furthermore, 202 attenuates nicotine self-administration and blocks nicotine prime-induced reinstatement in rats. Both in vitro selectivity and lack of agonist activity differentiateour compounds from varenicline and might produce fewer side effects. In this Phase I SBIR, we propose to optimize our lead compounds to further improve affinity, selectivity, and drug-like properties. In Specific Aim 1, we will synthesize additional novel analogs based upon the current lead scaffolds. In Specific Aim 2A we will determine binding affinities at 4 2 and 3 4 nAChR, using [3H]epibatidine to bind to membranes produced from HEK cells transfected with the appropriate receptors. Selectivity at additional nAChRs will be determined for the compounds exhibiting the highest affinity for 4 2 and the greatest selectivity against 3 4 nAChR. In Aim 2B we will determine the functional selectivity of compounds showing high affinity and selectivity in the binding assays. Antagonist activity and functional selectivity will be determined by measuring ligand-induced membrane potential changes using a FlexStation on intact HEK cells. Finally in Aim 2C we will measure bioavailability and blood brain barrier penetration to optimize drug-like properties of our lead compounds. These studies will be in preparation for subsequent in vivo efficacy determinations in nicotine reward models as well as additional pharmacokinetic studies, to be completed in a subsequent Phase II application.

描述（由申请人提供）：吸烟仍然是美国可避免的死亡原因。当前的疗法，包括尼古丁替代，对安非他酮的多巴胺系统抑制以及4 2个神经元烟碱乙酰胆碱受体（NACHR）的部分激活尚未特别有效，在接近80％的治疗药物或治疗中，复发率尚未特别有效。此外，Varenicline是最有效的药物，具有严重的精神病副作用。显然需要新的治疗方法。 NACHR与香烟的上瘾性最紧密相关的是4 2 NACHR。该受体的激活是尼古丁奖励的主要介体，并且已经证明了选择性但低亲和力4 2 NACHR拮抗剂DH E可以阻止啮齿动物模型中的尼古丁自我给药。目前尚无高亲和力和选择性4 2拮抗剂可作为戒烟药物。从包含超过500万个单个化合物的小分子组合库开始，我们已经确定了选择性4 2 NACHR化合物。使用这些筛选命中以及药物化学和分子建模，我们已经确定了两种铅化合物（2187.397和2187.202），一种具有很高的亲和力（37 nm）和中等选择性（23倍），在结合测定中进行中等选择性（23倍），第二个具有出色的选择性（> 500倍），但略低（500倍），但略低（500倍）（> 500倍）（114n 2 nach）。这两种化合物都是4 2个NACHR的拮抗剂，具有显着的体外选择性。体外功能测定表明，202在3 4 NACHR上的4 2处具有400倍的选择性。此外，202年减弱了尼古丁的自我给药，并阻止了尼古丁质量引起的大鼠恢复原状。体外选择性和缺乏激动剂活性都使化合物与Varenicline区分，并且可能产生更少的副作用。在此阶段I SBIR中，我们建议优化铅化合物，以进一步提高亲和力，选择性和类似药物样性能。在特定的目标1中，我们将根据当前的铅支架合成其他新型类似物。在特定的目标2a中，我们将使用[3H] epibatidine在4 2和3 4 NACHR处确定结合亲和力与与适当受体转染的HEK细胞产生的膜结合。将确定其他NACHR的选择性，该化合物对4 2的最高亲和力和对3 4 NACHR的最高选择性的选择性。在AIM 2B中，我们将确定在结合测定中显示出高亲和力和选择性的化合物的功能选择性。拮抗剂的活性和功能选择性将通过使用完整的HEK细胞上的弹性定位来测量配体诱导的膜电位变化来确定。最后，在AIM 2C中，我们将测量生物利用度和血脑屏障的穿透性，以优化铅化合物的药物样性能。这些研究将为随后的尼古丁奖励模型中的体内功效确定以及其他药代动力学研究做准备，并将在随后的II期应用中完成。