Abstract

Decades of research have highlighted the importance of optimal stimulation of cortical dopaminergic receptors, particularly the D1R receptor (D1R), for prefrontal-mediated cognition. This mechanism is particularly relevant to the cognitive deficits in schizophrenia, given the abnormalities in cortical dopamine (DA) neurotransmission and in the expression of D1R. Despite the critical need for D1R-based therapeutics, many factors have complicated their development and prevented this important therapeutic target from being adequately interrogated. Challenges include determination of the optimal level of D1R stimulation needed to improve cognitive performance, especially when D1R expression levels, affinity states, DA levels, and the resulting D1R occupancy by DA, are not clearly known in schizophrenia, and may display great interindividual and intraindividual variability related to cognitive states and other physiological variables. These directly affect the selection of the level of stimulation necessary to correct the underlying neurobiology. The optimal mechanism for stimulation is also unknown and could include partial or full agonism, biased agonism, or positive allosteric modulation. Furthermore, the development of D1R targeting drugs has been complicated by complexities in extrapolating from in vitro affinity determinations to in vivo use. Prior D1R-targeted drugs have been unsuccessful due to poor bioavailability, pharmacokinetics, and insufficient target engagement at tolerable doses. Newer drugs have recently become available, and these must be tested in the context of carefully designed paradigms that address methodological challenges. In this paper, we discuss how a better understanding of these challenges has shaped our proposed experimental design for testing a new D1R/D5R partial agonist, PF-06412562, renamed CVL-562.

中文翻译：

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多巴胺 D1R 受体刺激作为精神分裂症的机制促认知目标

摘要

数十年的研究强调了最佳刺激皮质多巴胺能受体，特别是 D1R 受体 (D1R)，对前额叶介导的认知的重要性。鉴于皮质多巴胺 (DA) 神经传递和 D1R 表达的异常，这种机制与精神分裂症的认知缺陷特别相关。尽管迫切需要基于 D1R 的疗法，但许多因素使它们的发展变得复杂，并阻止了这一重要的治疗靶点被充分研究。挑战包括确定提高认知能力所需的 D1R 刺激的最佳水平，特别是当 D1R 表达水平、亲和力状态、DA 水平以及由此产生的 DA 对 D1R 的占用在精神分裂症中尚不清楚时，并且可能表现出与认知状态和其他生理变量相关的巨大个体间和个体间变异性。这些直接影响纠正潜在神经生物学所需的刺激水平的选择。刺激的最佳机制也是未知的，可能包括部分或完全激动、偏向激动或正变构调节。此外，由于从体外亲和力测定外推到体内使用的复杂性，D1R 靶向药物的开发变得复杂。先前的 D1R 靶向药物由于生物利用度差、药代动力学和在可耐受剂量下靶点参与不足而未能成功。最近出现了较新的药物，这些必须在精心设计的范式背景下进行测试，以应对方法学挑战。在本文中，我们讨论了如何更好地理解这些挑战，从而塑造了我们提出的用于测试新的 D1R/D5R 部分激动剂 PF-06412562（更名为 CVL-562）的实验设计。