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- W2075825321 abstract "New drugs with enhanced electron donor properties that target the Ca2+ release channel (CRC) from sarcoplasmic reticulum are potent inhibitors of single channel activity. In this study we synthesize derivatives of the channel activator 4-chloro-3 methyl phenol (4-CmC) and the 1,4-benzothiazepine channel inhibitor K201 (JTV519) with enhanced electron donor properties. Instead of activating channel activity (∼100 uM), 4-CmC's 4-methoxy analog (4-methoxy-3-methyl phenol) inhibits channel activity at sub-micromolar concentrations (IC50 = 0.34 ± 0.08 uM). Increasing the electron donor characteristics of K201, by synthesizing its dioxole congener, results in a new compound which is 16 times more potent an inhibitor of single channel activity (0.24 ± 0.05 uM) than K201(3.98 ± 0.79 uM). These alterations to chemical structure do not affect Ca2+ dependent ATPase activity of SERCA1. Both K201 and its dioxole derivate show a similar potency toward inhibiting ATPase activity (IC50 ∼50 uM), while 4-methoxy-3-methyl phenol does not inhibit ATPase activity at concentrations up to 1 mM. Moreover, the FKBP12 protein, which stabilizes RyR1 in a closed configuration, is shown to be a strong electron donor. It appears as if FKBP12, K201, its dioxole derivative, and 4-methoxy-3-methyl phenol inhibit the skeletal muscle SR CRC channel activity by virtue of their electron donor characteristics. We also show that the inhibitory action of K201 is independent of FKBP12 binding to RyR1. These results embody strong evidence that designing new drugs that target the CRC with enhanced electron donor characteristics results in more potent channel inhibitors. This represents a novel approach toward designing new more potent drugs aimed at functionally modifying the CRC from sarcoplasmic reticulum. Supported by PSU Faculty Development Award, University Venture Development Fund, ONAMI, and NIH (R01 AR48911) to JJA." @default.
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- W2075825321 date "2011-02-01" @default.
- W2075825321 modified "2023-10-18" @default.
- W2075825321 title "Designing New Ca2+ Release Channel Inhibitors Based on Enhanced Electron Donor Characteristics" @default.
- W2075825321 doi "https://doi.org/10.1016/j.bpj.2010.12.2468" @default.
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