Activation of the sheep cardiac Ca2+ release channel by simple heteroaromatics.
The broad range of ligands known to modulate ryanodine receptor activity includes a class of heteroaromatic compounds displaying relatively poor efficacy. Greater understanding of the physicochemical properties that predispose these molecules to interaction with the channel should facilitate the rational design of more potent analogues. To this end we are examining the structure-activity relationship for simple heteroaromatic compounds. Efficacy is assessed by the ability to stimulate [3H]ryanodine binding to heavy sarcoplasmic reticulum vesicles. The propensity to activate the channel requires notably little chemical functionality and is associated with the capacity for charge-transfer complex formation in conjunction with steric bulk.
Bannister
Mark L
ML
Department of Cardiac Medicine, National Heart and Lung Institute, Imperial College London, Dovehouse Street, London SW3 6LY, UK.
Williams
Alan J
AJ
D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006841:Hydrocarbons, Aromatic / Q000494:pharmacology*; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D012756:Sheep; D013329:Structure-Activity Relationship
D006841:Hydrocarbons, Aromatic; D019837:Ryanodine Receptor Calcium Release Channel