Optimization of allosteric modulators of nicotinic receptors

烟碱受体变构调节剂的优化

• 批准号: 7241621
• 负责人: KELVIN W. GEE
• 金额: $ 21.39万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-09 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7241621
• 关键词: Adverse effects; Agonist; Alzheimer' s Disease; Amides; Aniline; Animal Model; Attention deficit hyperactivity disorder; Auditory; Auditory Evoked Potentials; Biological; Biological Assay; Brain; Bungarotoxins; Chemicals; Cholinergic Agents; Chromosomes, Human, Pair 15; Chronic; Clinical; Cognitive deficits; DBA/2 Mouse; Data; Development; Disease; Dose; Drug Kinetics; Electrons; Exposure to; Figs - dietary; GTS-21; Gated Ion Channel; Genetic; Goals; Halogens; Hippocampus (Brain); Human; In Vitro; Individual; Kinetics; Laboratories; Lead; Ligands; Link; Measures; Modeling; Modification; Neurons; Nicotine; Nicotinic Receptors; Oocytes; Patients; Pharmacodynamics; Physiologic pulse; Plasma; Population; Process; Protocols documentation; Pulse taking; Range; Receptor Activation; Relative (related person); Research; Rodent; Rodent Model; Role; Sampling; Schizophrenia; Selection Criteria; Sensory; Series; Specific qualifier value; Structure-Activity Relationship; Symptoms; System; Testing; Therapeutic; Therapeutic Agents; Time; Toxic effect; Treatment Protocols; Variant; acetylcholine receptor agonist; base; cholinergic; clinically relevant; design; drug discovery; experience; in vivo; interest; methyllycaconitine; mouse model; nervous system disorder; neurotoxic; neurotoxicity; phenylamide; pre-clinical; prototype; receptor; receptor function; research study; response; sensory gating; transmission process

DESCRIPTION (provided by applicant): Recent clinical and genetic studies provide strong evidence that spontaneous auditory gating deficits found in patients with schizophrenia maybe influenced by a7 nicotinic-acetylcholine receptors (nAChRs) located in the CA3 region of the hippocampus. Deficits in this auditory/sensory gating manifest as a sensory overload experience that can exacerbate both the positive and negative symptoms of schizophrenia. The human form of the auditory deficit is characterized by incomplete inhibitory processing of paired auditory evoked potentials spaced 50ms apart (P50). The P50 auditory deficit is genetically linked to the a7 nAChR locus on chromosome 15. Moreover, post-mortem analyses of schizophrenic brains indicate significant reductions in a7 nAChRs compared to normal individuals. The P50 auditory deficit is sensitive to cholinergic agents such as non-selective agonists (e.g., nicotine) and the selective a7 nAChRs agonist DMXB-A (GTS-21). In animal models, sensitivity to non-selective or selective a7 nAChR agonists is also blocked by selective a7 nAChR antagonists such as methyllycaconitine (MLA) or a-bungarotoxin but not a4¿2 selective antagonists such as dihydro-¿-ethroidine (DH¿E). The rodent P20-N40 auditory evoked potential (AEP) is analogous to the human P50 AEP and is a relevant model for assessing the effects of various pharmacological agents that may have utility to treat the sensory gating deficits of schizophrenia. Recent evidence using a rodent model of auditory gating deficit indicates that selective allosteric modulators of a7 nAChRs may boost the sensitivity of a7 nAChRs so that the gating deficit is rectified. However, the representative molecule in these proof-of-principle studies (PNU-120596) suffers from several attributes that make it unattractive as a therapeutic candidate. PNU-120596 is an allosteric modulator of a7 nAChRs which significantly alters the native kinetic response to agonist such that, in the presence of PNU-120596, a population of a7 nAChRs desensitized by high concentrations of nicotine can be re-sensitized. This is problematic since a7 nAChRs regulate Ca++ conductance. A large and sustained influx of Ca++ caused by the chronic presence of PNU-120596 in a treatment regimen is predicted to be neurotoxic. In contrast, our laboratory has developed selective a7 nAChR positive allosteric modulators which potentiate and preserve the native kinetics of receptor activation such that upon extended exposure to our compound desensitized a7 nAChRs remain as such. While the issue of retaining native kinetics of channel activity has been accomplished by our drug discovery efforts, we are uncertain as to what level of a7 nAChR efficacy is appropriate for therapeutic benefit in a setting where a7 nAChR function is already suboptimal (e.g., schizophrenia) while simultaneously avoiding Ca++-related neurotoxicity. The goal of the proposed research is to determine what minimum level of positive allosteric efficacy at a7 nAChRs is required to produce a reversal of P20-N40 auditory gating deficits in the DBA/2 mouse model of schizophrenia where a7 nAChR function is intrinsically compromised. Candidate molecules will be synthesized and tested in electrophysiological assays for enhancement of a7 nAChR currents elicited by nicotine to determine the structure activity relationships for maximum efficacy and potency relative to nicotine. The proposed molecules will show positive modulation of a7 nAChRs without activation of other nAChR subtypes (e.g., a4¿2, a3¿4) or other cys-loop ligand-gated ion channels (GABAA, 5HT3A). The pharmacokinetic (PK) profile of candidate molecules that fulfill our selection criteria for receptor subtype selectivity, potency and efficacy will be evaluated for whether appropriate brain levels (i.e., corresponding to maximum enhancement by the positive allosteric modulator observed in vitro) can be achieved. Completion of the proposed studies will establish the minimum extent of modulation of cholinergic transmission via a7 nAChRs necessary to correct a deficit of sensory inhibition in an animal model of schizophrenia. These results will help guide the pre-clinical development of potential candidate therapeutic agents that will be tested in schizophrenia and other neurological disorders (e.g., ADHD, Alzheimer's and other diseases involving cognitive deficit) that may be amenable to selective positive modulation of a7 nAChRs.

描述（由申请人提供）：最近的临床和遗传研究提供了强有力的证据，表明精神分裂症患者中发现的自发性听觉门控缺陷可能受到位于海马CA 3区的α 7烟碱乙酰胆碱受体（nAChR）的影响。这种听觉/感觉门控的缺陷表现为感觉超负荷体验，可加重精神分裂症的阳性和阴性症状。人类形式的听觉缺陷的特征在于间隔50 ms的成对听觉诱发电位（P50）的不完全抑制处理。P50听觉缺陷与15号染色体上的α 7 nAChR基因座遗传相关。此外，精神分裂症患者大脑的尸检分析表明，与正常个体相比，α 7 nAChR显著减少。P50听觉缺陷对胆碱能药物如非选择性激动剂（例如，尼古丁）和选择性α 7 nAChR激动剂DMXB-A（GTS-21）。在动物模型中，对非选择性或选择性α 7 nAChR激动剂的敏感性也可被选择性α 7 nAChR拮抗剂如甲基乌头碱（MLA）或α-银环蛇毒素阻断，但不能被α 4 <$2选择性拮抗剂如二氢-<$-乙脒（DH <$E）阻断。啮齿动物P20-N40听觉诱发电位（AEP）类似于人类P50 AEP，是一种用于评估各种药物作用的相关模型，这些药物可用于治疗精神分裂症的感觉门控缺陷。最近使用听觉门控缺陷的啮齿动物模型的证据表明，α 7 nAChR的选择性变构调节剂可以提高α 7 nAChR的敏感性，从而纠正门控缺陷。然而，这些原理验证研究（PNU-120596）中的代表性分子具有几个属性，使其作为治疗候选物没有吸引力。PNU-120596是α 7 nAChR的变构调节剂，其显著改变对激动剂的天然动力学响应，使得在PNU-120596存在下，被高浓度尼古丁脱敏的α 7 nAChR群体可以被重新敏化。这是有问题的，因为a7 nAChR调节Ca++电导。预测治疗方案中长期存在PNU-120596导致的大量持续Ca++内流具有神经毒性。相比之下，我们的实验室已经开发了选择性α 7 nAChR阳性变构调节剂，其增强并保持受体活化的天然动力学，使得在延长暴露于我们的化合物时，脱敏的α 7 nAChR保持原样。虽然通过我们的药物发现努力已经实现了保留通道活性的天然动力学的问题，但是我们不确定在α 7 nAChR功能已经是次优的情况下，什么水平的α 7 nAChR功效对于治疗益处是合适的（例如，精神分裂症），同时避免Ca++相关的神经毒性。所提出的研究的目标是确定在精神分裂症的DBA/2小鼠模型中产生P20-N40听觉门控缺陷的逆转所需的α 7 nAChR的正变构功效的最低水平，其中α 7 nAChR功能本质上受损。将合成候选分子，并在电生理学试验中检测尼古丁引起的α 7 nAChR电流增强，以确定相对于尼古丁的最大功效和效价的结构活性关系。所提出的分子将显示α 7 nAChR的正调节，而不激活其他nAChR亚型（例如，a4 <$2、a3 <$4）或其它cys环配体门控离子通道（GABAA、5 HT 3A）。将评价满足我们的受体亚型选择性、效力和功效的选择标准的候选分子的药代动力学（PK）特征，以确定是否存在适当的脑水平（即，对应于体外观察到的正变构调节剂的最大增强）。完成所提出的研究将确定通过α 7 nAChR调节胆碱能传递的最小程度，这是纠正精神分裂症动物模型中感觉抑制缺陷所必需的。这些结果将有助于指导潜在候选治疗药物的临床前开发，这些药物将在精神分裂症和其他神经系统疾病（例如，ADHD、阿尔茨海默氏症和涉及认知缺陷的其他疾病），其可能适合于α 7 nAChR的选择性正调节。