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- W2913302498 abstract "Calcium-/voltage-gated, large conductance potassium channels (BKs) are ubiquitously expressed. Smooth muscle (SM) BKs, which contain accessory beta1-subunits, regulate SM contractility. Upon activation, BKs generate outward K+ currents that counteract depolarization-induced Ca2+ entry and limit contraction. Given the rather specific expression of beta1-subunits in SM, their pharmacological targeting constitutes an attractive tool for selective modulation of SM BKs. We have previously identified a steroid-sensing site in BK beta1 that included Thr169 and Leu172,173. Herein, we advance non-steroidal analogs (NSTAs) that interact with this site but exert opposite effects on BK current and organ function. Based on a pharmacophore that described endogenous ligands for the BK beta1 steroid site (McMillan et al., 2014), we performed chemical library search to yield NSTAs. Hits were tested on BK currents using robotic patch-clamp. While some agents activated BK (decreased V0.5; “agonists”), others did not decrease or even increased V0.5 (collectively termed “antagonists”). Pharmacophore model refinement based on functional data led to development of two distinct pharmacophores: BK beta1 agonists hydrogen-bond with Thr169 and hydrophobically interact with Leu172,173. In contrast, antagonists lack the former feature while still forming hydrophobic interactions with Leu172,173. Both pharmacophores were used to search 400,000 structures in the ZINC database. The agonist pharmacophore matched 84 and the antagonist pharmacophore matched 131 chemically diverse compounds, with zero compounds matching both pharmacophores. Thus, our models have exquisite selectivity. Two antagonists that did not modify BK current effectively blunted BK activation and resulting dilation of rat cerebral arteries evoked by the beta1 Thr169-targeting lithocholic acid. Further optimization of BK beta1-targeting NSTA agonist-antagonist pairs will lead to the development of novel pharmaceuticals with potential to combat prevalent disorders where SM function is disrupted. R01 HL104631; R37 AA11560 (AMD)." @default.
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- W2913302498 date "2019-02-01" @default.
- W2913302498 modified "2023-09-30" @default.
- W2913302498 title "Development of BK Channel Agonists and Antagonists that Target a Common Recognition Area in the Accessory Beta1 Subunit" @default.
- W2913302498 doi "https://doi.org/10.1016/j.bpj.2018.11.2911" @default.
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