CCDI: a new ligand that modulates mammalian type 1 ryanodine receptor (RyR1).

Autor: Tian C; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA., Shao CH, Padanilam C, Ezell E, Singh J, Kutty S, Bidasee KR
Jazyk: angličtina
Zdroj: British journal of pharmacology [Br J Pharmacol] 2014 Sep; Vol. 171 (17), pp. 4097-111. Date of Electronic Publication: 2014 Jul 02.
DOI: 10.1111/bph.12764
Abstrakt: Background and Purpose: Ryanodine receptors (RyRs) are Ca(2+)-release channels on the sarco(endo)plasmic reticulum that modulate a wide array of physiological functions. Three RyR isoforms are present in cells: RyR1, RyR2 and RyR3. To date, there are no reports on ligands that modulate RyR in an isoform-selective manner. Such ligands are not only valuable research tools, but could serve as intermediates for development of therapeutics.
Experimental Approach: Pyrrole-2-carboxylic acid and 1,3-dicyclohexylcarbodiimide were allowed to react in carbon tetrachloride for 24 h at low temperatures and pressures. The chemical structures of the two products isolated were elucidated using NMR spectrometry, mass spectrometry and elemental analyses. [(3) H]-ryanodine binding, lipid bilayer and time-lapsed confocal imaging were used to determine their effects on RyR isoforms.
Key Results: The major product, 2-cyclohexyl-3-cyclohexylimino-2, 3, dihydro-pyrrolo[1,2-c]imidazol-1-one (CCDI) dose-dependently potentiated Ca(2+)-dependent binding of [(3)H]-ryanodine to RyR1, with no significant effects on [(3)H]-ryanodine binding to RyR2 or RyR3. CCDI also reversibly increased the open probability (P(o)) of RyR1 with minimal effects on RyR2 and RyR3. CCDI induced Ca(2+) transients in C2C12 skeletal myotubes, but not in rat ventricular myocytes. This effect was blocked by pretreating cells with ryanodine. The minor product 2-cyclohexyl-pyrrolo[1,2-c]imidazole-1,3-dione had no effect on either [(3)H]-ryanodine binding or P(o) of RyR1, RyR2 and RyR3.
Conclusions and Implications: A new ligand that preferentially modulates RyR1 was identified. In addition to being an important research tool, the pharmacophore of this small molecule could serve as a template for the synthesis of other isoform-selective modulators of RyRs.
(© 2014 The British Pharmacological Society.)
Databáze: MEDLINE
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