Ryanodine action at calcium release channels. 1. importance of hydroxyl substituents.
Ryanodine (1) and dehydroryanodine (2) have a polar face formed by cis-hydroxyls at C-2, C-4, C-6, and C-12. The importance of the hydroxyls to the action of 1 and 2 at the ryanodine receptor (ryr) of calcium release channels is examined at [3H]-1 binding sites in brain and skeletal muscle and in heart membranes relative to cardiac contractility, a pharmacologic response which appears to be mediated by the ryr. Five types of changes are considered: blocking the 4- and 6-hydroxyls as cyclic borates and boronates; blocking the 10- and 12-hydroxyls as cyclic phosphates, phosphonates, and phosphoramidates; methylation at nitrogen or hydroxyls at C-4 and C-10; dehydration of the C-2 hydroxyl; additional data for a 4,12-oxygen-bridged series. The first change has little effect on potency possibly due to the lability of the boron protective groups whereas the cyclic phosphorus compounds have reduced activity. Methylation reduces potency the least at nitrogen and the C-4 hydroxyl. Dehydration of 1 to 2-deoxy-2(13)-dehydro-1 allows the restoration of oxygen at C-2 by conversion to epoxides or a diol. One of the epoxides and 2-deoxy-2(13)-dehydro-2 retain 8-31% of ryanodine's potency in the ryr assays and 81% in the cardiac contractility system. In the 4,12-oxygen-bridged series, high potency at the receptor and cardiac muscle is retained in the 4-hydroxy ketal.
Jefferies
P R
PR
Department of Environmental Science, Policy, and Management, University of California, Berkeley 94720-3112, USA.
Blumenkopf
T A
TA
Gengo
P J
PJ
Cole
L C
LC
Casida
J E
JE
D000818:Animals; D001896:Boron Compounds / Q000378:metabolism / Q000494:pharmacology; D001923:Brain Chemistry; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects*; D004285:Dogs; D004852:Epoxy Compounds / Q000378:metabolism / Q000494:pharmacology; D006878:Hydroxides / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008745:Methylation; D051379:Mice; D015394:Molecular Structure; D009124:Muscle Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects*; D009200:Myocardial Contraction / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects; D010100:Oxygen / Q000378:metabolism; D010766:Phosphorylation; D011817:Rabbits; D051381:Rats; D012433:Ryanodine / Q000494:pharmacology*; D019837:Ryanodine Receptor Calcium Release Channel; D013329:Structure-Activity Relationship
D001896:Boron Compounds; D015220:Calcium Channels; D004852:Epoxy Compounds; D006878:Hydroxides; D009124:Muscle Proteins; D009419:Nerve Tissue Proteins; D019837:Ryanodine Receptor Calcium Release Channel; D012433:Ryanodine; C031356:hydroxide ion; D010100:Oxygen; D002118:Calcium