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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 LCAlateral 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.
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