Compounds and methods for modulating activity of calcium release channels
View Patent ↗The present teachings provide compounds of Formulae I and II: and pharmaceutically acceptable salts, hydrates, complexes, esters, and prodrugs thereof, wherein R 1 , R 1′ , R 2 , R 2′ , R 3 , R 3′ , and X are as defined herein. The present teachings also provide methods of making the compounds of formulae I and II, and methods of treating RyR-associated conditions, disorders, and diseases that include administering a therapeutically effective amount of a compound of formula I or II to a subject in need thereof. In addition, the present teachings relate to methods of reducing the open probability of a ryanodine receptor, and methods of reducing Ca 2+ release across a ryanodine receptor (e.g., into the cytoplasm of a cell), by contacting a compound of formula I or II with a ryanodine receptor.
1. A method for modulating a ryanodine receptor (RyR) that regulates calcium channel functioning in a cell, the method comprising contacting a cell with an effective amount of a compound having the formula
or a pharmaceutically acceptable salt, hydrate, ester, or prodrug thereof;
wherein X is an electron-donating group selected from OH, OR 5 , SH, SR 5 , NH 2 , NHR 5 , NRSR 5′ , or a C 1-10 alkyl group substituted with 1-4 groups independently selected from OH, OR 5 , SH, SR 5 , NH 2 , NHR 5 , and NRSRS′; and R 5 and R 5′ are identical or different C 1-10 alkyl groups.
2. The method of claim 1 wherein X is —OCH 3 .
3. The method of claim 1 wherein:
X is OH, OR 5 , NH 2 , NHR 5 , or NR 5 R 5′ ; and
R 5 and R 5 ′ independently are a methyl group, an ethyl group, an n-propyl group, an iso-propyl group, an n-butyl group, an iso-butyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, an iso-pentyl group, or a neo-pentyl group.
4. The method of claim 3 wherein R 5 and R 5′ are methyl.
5. The method of claim 1 , wherein the effective amount is <5 μM.
6. The method of claim 5 wherein X is —OCH 3 , and the effective amount is 2-5 μM.
7. The method of claim 1 wherein the compound modifies thiol/disulfide balance within ryanodine receptors in the cell.
8. The method of claim 1 , wherein the cell is a muscle cell.
9. The method of claim 8 wherein the compound decreases intracellular Ca 2+ release in the muscle cell.
10. The method of claim 7 wherein the muscle cell is a skeletal muscle cell or a cardiac muscle cell.
11. The method of claim 8 wherein the compound reduces the open probability of ryanodine receptors in a skeletal muscle cell.
12. The method of claim 8 wherein the compound reduces the open probability of ryanodine receptors in a cardiac muscle cell.