Free R Benjamin, Nilson Ashley N, Boldizsar Noelia M, Doyle Trevor B, Rodriguiz Ramona M, Pogorelov Vladimir M, Machino Mayako, Lee Kuo Hao, Bertz Jeremiah W, Xu Jinbin, Lim Herman D, Dulcey Andrés E, Mach Robert H, Woods James H, Lane J Robert, Shi Lei, Marugan Juan J, Wetsel William C, Sibley David R
Molecular Neuropharmacology Section, National Institute of Neurological Disorders and Stroke, Intramural Research Program, National Institutes of Health, 35 Convent Drive, MSC-3723, Bethesda, Maryland20892, United States.
Department of Psychiatry and Behavioral Sciences, Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, 354 Sands Building, 303 Research Drive, Durham, North Carolina27710, United States.
ACS Pharmacol Transl Sci. 2022 Dec 30;6(1):151-170. doi: 10.1021/acsptsci.2c00202. eCollection 2023 Jan 13.
We have developed and characterized a novel D2R antagonist with exceptional GPCR selectivity - ML321. In functional profiling screens of 168 different GPCRs, ML321 showed little activity beyond potent inhibition of the D2R and to a lesser extent the D3R, demonstrating excellent receptor selectivity. The D2R selectivity of ML321 may be related to the fact that, unlike other monoaminergic ligands, ML321 lacks a positively charged amine group and adopts a unique binding pose within the orthosteric binding site of the D2R. PET imaging studies in non-human primates demonstrated that ML321 penetrates the CNS and occupies the D2R in a dose-dependent manner. Behavioral paradigms in rats demonstrate that ML321 can selectively antagonize a D2R-mediated response (hypothermia) while not affecting a D3R-mediated response (yawning) using the same dose of drug, thus indicating exceptional selectivity. We also investigated the effects of ML321 in animal models that are predictive of antipsychotic efficacy in humans. We found that ML321 attenuates both amphetamine- and phencyclidine-induced locomotor activity and restored pre-pulse inhibition (PPI) of acoustic startle in a dose-dependent manner. Surprisingly, using doses that were maximally effective in both the locomotor and PPI studies, ML321 was relatively ineffective in promoting catalepsy. Kinetic studies revealed that ML321 exhibits slow-on and fast-off receptor binding rates, similar to those observed with atypical antipsychotics with reduced extrapyramidal side effects. Taken together, these observations suggest that ML321, or a derivative thereof, may exhibit ″atypical″ antipsychotic activity in humans with significantly fewer side effects than observed with the currently FDA-approved D2R antagonists.
我们已经开发并表征了一种具有卓越GPCR选择性的新型D2R拮抗剂——ML321。在对168种不同GPCR的功能分析筛选中，ML321除了对D2R有强效抑制作用外，对其他受体几乎没有活性，对D3R的抑制作用较小，显示出优异的受体选择性。ML321对D2R的选择性可能与以下事实有关：与其他单胺能配体不同，ML321缺乏带正电荷的胺基，并在D2R的正构结合位点内采取独特的结合姿势。在非人类灵长类动物中的PET成像研究表明，ML321能够穿透中枢神经系统，并以剂量依赖性方式占据D2R。大鼠的行为范式表明，使用相同剂量的药物，ML321可以选择性地拮抗D2R介导的反应（体温过低），而不影响D3R介导的反应（打哈欠），从而表明其具有卓越的选择性。我们还研究了ML321在预测人类抗精神病疗效的动物模型中的作用。我们发现，ML321能以剂量依赖性方式减弱苯丙胺和苯环己哌啶诱导的运动活性，并恢复听觉惊吓的前脉冲抑制（PPI）。令人惊讶的是，在运动和PPI研究中使用最大有效剂量时，ML321在促进僵住症方面相对无效。动力学研究表明，ML321表现出缓慢结合和快速解离的受体结合速率，类似于那些具有减少锥体外系副作用的非典型抗精神病药物所观察到的速率。综上所述，这些观察结果表明，ML321或其衍生物在人类中可能表现出“非典型”抗精神病活性，且副作用明显少于目前FDA批准的D2R拮抗剂。
