D1 dopamine receptor positive allosteric modulators as a practical treatment for cognitive decline

标题：D1多巴胺受体阳性变构调节剂作为认知功能减退的实用治疗 总结：D1多巴胺（DA）受体（D1 R）的激活是阿尔茨海默病或其他疾病（如精神分裂症和帕金森病）中观察到的认知能力下降的一种有前途的治疗策略。Goldman-Rakic及其同事的工作表明，前额叶皮层（PFC）中D1 R活性的最佳水平是学习和记忆的最佳表现所必需的。这导致了PFC中D1 R活性与认知功能关系的倒U型假设。在低水平的D1 R信号传导下，例如在疾病状态下，认知功能是次优的。在压力期间观察到的极高水平的D1 R活性，认知功能也处于次优水平。D1 R激动剂已经在阿尔茨海默病模型中显示出改善认知下降的有希望的功效，然而，正构D1 R激动剂固有的临床倾向限制了它们的治疗转化。D1 R正变构调节剂（PAM）具有高选择性、更大的治疗窗和降低的耐受性的潜力。我们已经从高通量筛选（HTS）中确定了四种结构上不同的命中支架。初步药理学表征已经验证了这些命中作为D1 R PAM化合物，其本身没有可测量的D1 R激动作用。该提案的重点是选择性地将这些命中化合物推进为治疗先导物。 所有四个HTS命中物在结构上不同于已知的DA配体，并且它们的D1 R PAM活性已经被再次确认。两个命中（噻吩和嘧啶酮为基础的化合物）已在广泛的药理学研究中进一步表征。这两种化合物增强DA刺激的G蛋白和抑制蛋白介导的信号传导，并增加DA对D1 R的亲和力。噻吩命中已被证明是有用的化学工具，并使我们能够确定第二个D1 R变构结合位点，据我们所知，这是独特的这个支架。当组合测试时，基于噻吩和嘧啶酮的PAM两者的最大有效浓度比单独的PAM更大程度地增强DA刺激的信号传导。这些数据是很难解释的，而不调用存在两个D1 R变构位点，独立地介导的行动，这两个不同的PAM。用化合物B和DETQ（分别由Bristol-Myers Squibb和Eli Lilly开发的已知的细胞内环2（ICL 2）结合D1 R PAM）重复这样的组合实验。化合物B和DETQ都与噻吩化学型相加，但与嘧啶酮化学型不相加，进一步表明D1 R具有至少两个单独的PAM结合位点。我们努力的一个主要重点将是优化噻吩击中支架，靶向D1 R内的一个新的和未探索的变构位点，以促进治疗线索的开发。D1 R PAM的治疗潜力和迄今为止的累积证据支持对新支架的进一步研究和有前景的先导化合物的药理学表征。这种系统的方法将提供最先进的工具分子来研究D1 R变构位点以及推进D1 R PAM的治疗效用。

Title: D1 dopamine receptor positive allosteric modulators as a practical treatment for cognitive decline Summary: Activation of the D1 dopamine (DA) receptor (D1R) is a promising treatment strategy for the cognitive decline observed in Alzheimer’s disease or other disorders such as schizophrenia and Parkinson’s disease. Work by Goldman-Rakic and colleagues has shown that an optimum level of D1R activity in the prefrontal cortex (PFC) is required for optimum performance in learning and memory. This has led to the inverted-U hypothesis for the relationship of D1R activity in the PFC and cognitive function. At low levels of D1R signaling, such as in diseased states, cognitive function is suboptimum. At extremely high levels of D1R activity, as observed during stress, cognitive function is also at suboptimum levels. D1R agonists have shown promising efficacy in Alzheimer’s disease models for ameliorating cognitive decline, however the clinical liability inherent with orthosteric D1R agonists has limited their therapeutic translation. D1R positive allosteric modulators (PAMs) have the potential for high selectivity, larger therapeutic windows and reduced tolerance. We have identified four structurally distinct hit scaffolds from high-throughput screening (HTS). Preliminary pharmacological characterization has validated these hits as D1R PAM compounds with no measurable D1R agonism on their own. The focus of this proposal is to selectively advance these hit compounds into therapeutic leads. All four HTS hits are structurally distinct from known DA ligands and their D1R PAM activities have been reconfirmed. Two hits (thiophene- and pyrimidone-based compounds) have been further characterized in a wide range of pharmacological studies. Both compounds potentiate DA-stimulated G protein- and -arrestin-mediated signaling and increase the affinity of DA for the D1R. The thiophene hit has proven useful as a chemical tool and allowed us to identify a second D1R allosteric binding site that, to our knowledge, is unique to this scaffold. When tested in combination, maximally effective concentrations of both thiophene- and pyrimidone-based PAMs potentiate DA-stimulated signaling to a greater extent than either PAM alone. These data are difficult to explain without invoking the existence of two D1R allosteric sites that independently mediate the actions of these two different PAMs. Such combination experiments were repeated with Compound B and DETQ, known intracellular loop 2 (ICL2)-binding D1R PAMs that were developed by Bristol-Myers Squibb and Eli Lilly, respectively. Both Compound B and DETQ were additive with the thiophene chemotype, but not with the pyrimidone chemotype, further suggesting that the D1R has at least two separate PAM binding sites. A major focus of our efforts will be to optimize the thiophene hit scaffold that targets a novel and unexplored allosteric site within the D1R to facilitate the development of therapeutic leads. The therapeutic potential for D1R PAMs and the cumulative evidence to date supports further investigation of new scaffolds and the pharmacological characterization of promising lead compounds. Such a systematic approach will provide state-of-the-art tool molecules to investigate D1R allosteric sites as well as advance the therapeutic utility of D1R PAMs.