AMINOACRYLRYANODINES AND GUANIDINOACYLRYANODINES - BASIC RYANODINE ESTERS WITH ENHANCED AFFINITY FOR THE SARCOPLASMIC-RETICULUM CA2-RELEASECHANNEL()

Amino- and guanidinoacyl esters of ryanodine were prepared to evaluate the effect of basicity on the binding affinity of these derivatives f or the sarcoplasmic reticulum Ca2+-release channel (SR CRC). In the pr esence of DCC and DMAP Cbz-beta-alanine reacts with ryanodine in CH2Cl 2 to give O10eq-Cbz-beta-alanylryanodine (3a), which on hydrogenolysis yields the beta-alanyl ester (4a). N,N'-bis-Cbz-S-methylthiourea reac ts with 4a to yield beta-N,N'-bis-Cbz-guanidinopropionylryanodine (5a) . O10eq-beta-guanidinopropionylryanodine (6a) is obtained on hydrogeno lytic 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-fo ld greater, than that of ryanodine. The effect of ryanodine on SR Ca2 flux is of a biphasic nature: nanomolar levels open (activate) the ch annel, while micromolar levels close (deactivate) it. The base-substit uted esters 4a and 6a both display a unidirectional effect: they only open the channel. An understanding of ryanodine's mode of action and t he design of effective SR CRC activating and deactivating ryanoids for possible therapeutic application are major research objectives.