Department of Pharmacology, College of Medicine, The University of Arizona , Tucson, AZ, USA.
Bright Rock Path Consulting, LLC , Tucson, AZ, USA.
Channels (Austin). 2021 Dec;15(1):128-135. doi: 10.1080/19336950.2020.1863595.
Structural studies with an α subunit fragment of voltage-gated calcium (CaV) channels in complex with the CaVβ subunits revealed a high homology between the various CaVα-β subunits, predicting that targeting of this interface would result in nonselective compounds. Despite this likelihood, my laboratory initiated a rational structure-based screening campaign focusing on "hot spots" on the alpha interacting domain (AID) of the CaVβ2a subunits and identified the small molecule 2-(3,5-dimethylisoxazol-4-yl)-N-((4-((3-phenylpropyl)amino)quinazolin-2-yl)methyl)acetamide ( ) which selectively targeted the interface between the N-type calcium (CaV2.2) channel and CaVβ. (i) specifically bound to CaVβ2a; (ii) inhibited CaVβ2 's interaction with CaV.2-AID; (iii) inhibited CaV2.2 currents in sensory neurons; (iv) inhibited pre-synaptic localization of CaV2.2 ; and (v) inhibited spinal neurotransmission, which resulted in decreased neurotransmitter release. was anti-nociceptive in naïve rats and reversed mechanical allodynia and thermal hyperalgesia in rodent models of acute, neuropathic, and genetic pain. In structure-activity relationship (SAR) studies focused on improving binding affinity of , another compound (BTT-369), a benzoyl-3,4-dihydro-1'H,2 H-3,4'-bipyrazole class of compounds, was reported by Chen and colleagues, based on work conducted in my laboratory beginning in 2008. BTT-369 contains tetraaryldihydrobipyrazole scaffold - a chemotype featuring phenyl groups known to be significantly metabolized, lower the systemic half-life, and increase the potential for toxicity. Furthermore, the benzoylpyrazoline skeleton in BTT-369 is patented across multiple therapeutic indications. Prior to embarking on an extensive optimization campaign of , we performed a head-to-head comparison of the two compounds. We conclude that is superior to BTT-369 for on-target efficacy, setting the stage for SAR studies to improve on for the development of novel pain therapeutics.
电压门控钙 (CaV) 通道的 α 亚基片段与 CaVβ 亚基复合物的结构研究表明，各种 CaVα-β 亚基之间具有高度同源性，预测靶向该界面将产生非选择性化合物。尽管有这种可能性，但我的实验室启动了一项基于理性结构的筛选活动，重点关注 CaVβ2a 亚基的α相互作用域 (AID) 上的“热点”，并确定了小分子 2-(3,5-二甲基异恶唑-4-基)-N-((4-((3-苯基丙基)氨基)喹唑啉-2-基)甲基)乙酰胺 ( )，它选择性地靶向 N 型钙 (CaV2.2) 通道和 CaVβ 之间的界面。(i) 特异性结合 CaVβ2a；(ii) 抑制 CaVβ2 与 CaV2.2-AID 的相互作用；(iii) 抑制感觉神经元中的 CaV2.2 电流；(iv) 抑制 CaV2.2 的前突触定位；(v) 抑制脊髓神经传递，导致神经递质释放减少。在无经验的大鼠中具有抗伤害感受作用，并逆转了急性、神经性和遗传性疼痛模型中机械性痛觉过敏和热痛觉过敏。在基于结构的活性关系 (SAR) 研究中，重点是提高 的结合亲和力，Chen 及其同事报道了另一种化合物 (BTT-369)，一种苯甲酰基-3,4-二氢-1'H,2'H-3,4'-联吡唑类化合物，基于我实验室从 2008 年开始进行的工作。BTT-369 含有四芳基二氢联吡唑骨架 - 一种包含已知会被显著代谢、降低系统半衰期和增加毒性潜力的苯基的化学型。此外，BTT-369 中的苯甲酰基吡唑啉骨架在多个治疗适应症中获得专利。在开始广泛优化 之前，我们对这两种化合物进行了直接比较。我们的结论是，在针对目标的疗效方面，优于 BTT-369，为 SAR 研究奠定了基础，以提高新型疼痛治疗药物的开发。
