Amino- and guanidinoacylryanodines: basic ryanodine esters with enhanced affinity for the sarcoplasmic reticulum Ca(2+)-release channel.
Amino- and guanidinoacyl esters of ryanodine were prepared to evaluate the effect of basicity on the binding affinity of these derivatives for the sarcoplasmic reticulum Ca(2+)-release channel (SR CRC). In the presence of DCC and DMAP Cbz-beta-alanine reacts with ryanodine in CH2Cl2 to give O10eq-Cbz-beta-alanylryanodine (3a), which on hydrogenolysis yields the beta-alanyl ester (4a). N,N'-bis-Cbz-S-methylthiourea reacts with 4a to yield beta-N,N'-bis-Cbz-guanidinopropionylryanodine (5a). O10eq-beta-guanidinopropionylryanodine (6a) is obtained on hydrogenolytic deprotection of 5a. The binding affinity of beta-alanine ester (4a) and its glycyl congener (4b) is 2-3-fold greater, and that of the beta-guanidinopropionyl ester (6a) and its acetyl congener (6b) 3-6-fold greater, than that of ryanodine. The effect of ryanodine on SR Ca2+ flux is of a biphasic nature: nanomolar levels open (activate) the channel, while micromolar levels close (deactivate) it. The base-substituted esters 4a and 6a both display a unidirectional effect: they only open the channel. An understanding of ryanodine's mode of action and the design of effective SR CRC activating and deactivating ryanoids for possible therapeutic application are major research objectives.
Department of Pharmacology and Toxicology, Indiana University, School of Medicine, Indianapolis 46202.
K
K
Gerzon
R A
RA
Humerickhouse
H R
HR
Besch
K R
KR
Bidasee
J T
JT
Emmick
R W
RW
Roeske
Z
Z
Tian
L
L
Ruest
J L
JL
Sutko
D000596:Amino Acids / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D015220:Calcium Channels / Q000187:drug effects*; D004952:Esters / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D006146:Guanidines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011817:Rabbits; D012433:Ryanodine / Q000031:analogs & derivatives*; D012519:Sarcoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
D000596:Amino Acids; D015220:Calcium Channels; D004952:Esters; D006146:Guanidines; D012433:Ryanodine