{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T18:33:26Z","timestamp":1774550006229,"version":"3.50.1"},"reference-count":48,"publisher":"Wiley","issue":"17","license":[{"start":{"date-parts":[[2014,7,2]],"date-time":"2014-07-02T00:00:00Z","timestamp":1404259200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100006518","name":"University of Nebraska Medical Center","doi-asserted-by":"crossref","award":["No Number"],"award-info":[{"award-number":["No Number"]}],"id":[{"id":"10.13039\/100006518","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2014,9]]},"abstract":"Background and Purpose<\/jats:title>Ryanodine receptors (R<\/jats:styled-content>yR<\/jats:styled-content>s) areCa<\/jats:roman>2+<\/jats:sup><\/jats:styled-content>\u2010release channels on the sarco(endo)plasmic reticulum that modulate a wide array of physiological functions. ThreeR<\/jats:styled-content>yR<\/jats:styled-content>isoforms are present in cells:R<\/jats:styled-content>yR<\/jats:styled-content>1,R<\/jats:styled-content>yR<\/jats:styled-content>2 andR<\/jats:styled-content>yR<\/jats:styled-content>3. To date, there are no reports on ligands that modulateR<\/jats:styled-content>yR<\/jats:styled-content>in an isoform\u2010selective manner. Such ligands are not only valuable research tools, but could serve as intermediates for development of therapeutics.<\/jats:p><\/jats:sec>Experimental approach<\/jats:title>Pyrrole\u20102\u2010carboxylic acid and 1,3\u2010dicyclohexylcarbodiimide were allowed to react in carbon tetrachloride for 24\u2009h at low temperatures and pressures. The chemical structures of the two products isolated were elucidated using NMR spectrometry, mass spectrometry and elemental analyses. [3<\/jats:sup>H<\/jats:styled-content>]\u2010ryanodine binding, lipid bilayer and time\u2010lapsed confocal imaging were used to determine their effects onR<\/jats:styled-content>yR<\/jats:styled-content>isoforms.<\/jats:p><\/jats:sec>Key results<\/jats:title>The major product, 2\u2010cyclohexyl\u20103\u2010cyclohexylimino\u20102, 3, dihydro\u2013pyrrolo[1,2\u2010c<\/jats:italic>]imidazol\u20101\u2010one (CCDI<\/jats:styled-content>) dose\u2010dependently potentiatedCa<\/jats:roman>2+<\/jats:sup><\/jats:styled-content>\u2010dependent binding of [3<\/jats:sup>H<\/jats:styled-content>]\u2010ryanodine toR<\/jats:styled-content>yR<\/jats:styled-content>1, with no significant effects on [3<\/jats:sup>H<\/jats:styled-content>]\u2010ryanodine binding toR<\/jats:styled-content>yR<\/jats:styled-content>2 orR<\/jats:styled-content>yR<\/jats:styled-content>3.CCDI<\/jats:styled-content>also reversibly increased the open probability (P<\/jats:styled-content>o<\/jats:sub>) ofR<\/jats:styled-content>yR<\/jats:styled-content>1 with minimal effects onR<\/jats:styled-content>yR<\/jats:styled-content>2 andR<\/jats:styled-content>yR<\/jats:styled-content>3.CCDI<\/jats:styled-content>inducedCa<\/jats:roman>2+<\/jats:sup><\/jats:styled-content>transients inC<\/jats:styled-content>2C<\/jats:styled-content>12 skeletal myotubes, but not in rat ventricular myocytes. This effect was blocked by pretreating cells with ryanodine. The minor product 2\u2010cyclohexyl\u2010pyrrolo[1,2\u2010c<\/jats:italic>]imidazole\u20101,3\u2010dione had no effect on either [3<\/jats:sup>H<\/jats:styled-content>]\u2010ryanodine binding orP<\/jats:styled-content>o<\/jats:sub>ofR<\/jats:styled-content>yR<\/jats:styled-content>1,R<\/jats:styled-content>yR<\/jats:styled-content>2 andR<\/jats:styled-content>yR<\/jats:styled-content>3.<\/jats:p><\/jats:sec>Conclusions and implications<\/jats:title>A new ligand that preferentially modulatesR<\/jats:styled-content>yR<\/jats:styled-content>1 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\u2010selective modulators ofR<\/jats:styled-content>yR<\/jats:styled-content>s.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.12764","type":"journal-article","created":{"date-parts":[[2014,5,13]],"date-time":"2014-05-13T03:48:38Z","timestamp":1399952918000},"page":"4097-4111","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["CCDI<\/scp>: a new ligand that modulates mammalian type 1 ryanodine receptor (R<\/scp>yR<\/scp>1)"],"prefix":"10.1111","volume":"171","author":[{"given":"Chengju","family":"Tian","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience University of Nebraska Medical Center Omaha Nebraska USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chun 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