Department of Pharmacology, College of Medicine, University of Tennessee Health Science Center, 874 Union Ave, #115, Memphis, TN 38163, USA.
ChemMedChem. 2012 Oct;7(10):1784-92. doi: 10.1002/cmdc.201200290. Epub 2012 Sep 4.
Large conductance, calcium- and voltage-gated potassium (BK) channels regulate various physiological processes and represent an attractive target for drug discovery. Numerous BK channel activators are available. However, these agents usually interact with the ubiquitously distributed channel-forming subunit and thus cannot selectively target a particular tissue. We performed a structure-activity relationship study of lithocholic acid (LCA), a cholane that activates BK channels via the accessory BK β1 subunit. The latter protein is highly abundant in smooth muscle but scarce in most other tissues. Modifications to the LCA lateral chain length and functional group yielded two novel smooth muscle BK channel activators in which the substituent at C24 has a small volume and a net negative charge. Our data provide detailed structural information that will be useful to advance a pharmacophore in search of β1 subunit-selective BK channel activators. These compounds are expected to evoke smooth muscle relaxation, which would be beneficial in the pharmacotherapy of prevalent human disorders associated with increased smooth muscle contraction, such as systemic hypertension, cerebral or coronary vasospasm, bronchial asthma, bladder hyperactivity, and erectile dysfunction.
大电导、钙和电压门控钾 (BK) 通道调节各种生理过程，是药物发现的一个有吸引力的靶点。有许多 BK 通道激活剂。然而，这些药物通常与广泛分布的形成通道的亚基相互作用，因此不能选择性地针对特定组织。我们对胆酸（LCA）进行了构效关系研究，胆酸通过辅助 BK β1 亚基激活 BK 通道。后者在平滑肌中含量丰富，但在大多数其他组织中含量很少。对 LCA 侧链长度和官能团的修饰得到了两种新型的平滑肌 BK 通道激活剂，其中 C24 位的取代基体积小，净负电荷。我们的数据提供了详细的结构信息，这将有助于推进寻找β1 亚基选择性 BK 通道激活剂的药效团。这些化合物有望引起平滑肌松弛，这将有益于治疗与平滑肌收缩增加相关的常见人类疾病的药物治疗，例如高血压、脑或冠状动脉痉挛、支气管哮喘、膀胱过度活动症和勃起功能障碍。
