Department of Pharmacology and Toxicology and Center of Molecular Biosciences, University of Innsbruck, Innsbruck, Austria.
Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Innsbruck, Innsbruck, Austria.
Br J Pharmacol. 2023 May;180(10):1289-1303. doi: 10.1111/bph.16060. Epub 2023 Mar 14.
Voltage-gated L-type Ca -channels (LTCCs) are the target of Ca -channel blockers (CCBs), which are in clinical use for the evidence-based treatment of hypertension and angina. Their cardiovascular effects are largely mediated by the Ca 1.2-subtype. However, based on our current understanding of their physiological and pathophysiological roles, Ca 1.3 LTCCs also appear as attractive drug targets for the therapy of various diseases, including treatment-resistant hypertension, spasticity after spinal cord injury and neuroprotection in Parkinson's disease. Since CCBs inhibit both Ca 1.2 and Ca 1.3, Ca 1.3-selective inhibitors would be valuable tools to validate the therapeutic potential of Ca 1.3 channel inhibition in preclinical models. Despite a number of publications reporting the discovery of Ca 1.3-selective blockers, their selectivity remains controversial. We conclude that at present no pharmacological tools exist that are suitable to confirm or refute a role of Ca 1.3 channels in cellular responses. We also suggest essential criteria for a small molecule to be considered Ca 1.3-selective.
电压门控 L 型钙通道 (LTCCs) 是钙通道阻滞剂 (CCBs) 的作用靶点，CCBs 已被临床用于基于证据的高血压和心绞痛治疗。它们的心血管作用主要由 Ca 1.2 亚型介导。然而，根据我们目前对其生理和病理生理作用的理解，Ca 1.3 LTCC 也似乎是治疗各种疾病的有吸引力的药物靶点，包括治疗抵抗性高血压、脊髓损伤后的痉挛和帕金森病的神经保护。由于 CCB 抑制 Ca 1.2 和 Ca 1.3，因此 Ca 1.3 选择性抑制剂将是验证 Ca 1.3 通道抑制在临床前模型中的治疗潜力的有价值的工具。尽管有许多出版物报道了 Ca 1.3 选择性阻滞剂的发现，但它们的选择性仍然存在争议。我们的结论是，目前没有合适的药理学工具来证实或反驳 Ca 1.3 通道在细胞反应中的作用。我们还提出了小分子被认为是 Ca 1.3 选择性的基本标准。
