Amino- and Guanidinoacylryanodines

Basic Ryanodine Esters with Enhanced Affinity for the Sarcoplasmic Reticulum Ca2+-Release Channel

Koert Gerzon, Rod A. Humerickhouse, Henry R. Besch, Keshore R Bidasee, Jeffrey T. Emmick, Roger W. Roeske, Zhenping Tian, Luc Ruest, John L. Sutko

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

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 Ca2+-release channel (SR CRC). In the presence of DCC and DMAP Cbz-β-alanine reacts with ryanodine in CH2C12 to give O10eq-Cbz-β-alanylryanodine (3a), which on hydrogenolysis yields the β-alanyl ester (4a). N,N′-bis-Cbz-S-methylthiourea reacts with 4a to yield β-N,N′-bis-Cbz-guanidinopropionylryanodine (5a). O10eq-β-guanidinopropionylryanodine (6a) is obtained on hydrogenolytic deprotection of 5a. The binding affinity of β-alanine ester (4a) and its glycyl congener (4b) is 2–3-fold greater, and that of the β-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.

Original languageEnglish (US)
Pages (from-to)1319-1323
Number of pages5
JournalJournal of Medicinal Chemistry
Volume36
Issue number10
DOIs
StatePublished - Jan 1 1993

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Ryanodine
Sarcoplasmic Reticulum
Esters
Alanine
Research

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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Amino- and Guanidinoacylryanodines : Basic Ryanodine Esters with Enhanced Affinity for the Sarcoplasmic Reticulum Ca2+-Release Channel. / Gerzon, Koert; Humerickhouse, Rod A.; Besch, Henry R.; Bidasee, Keshore R; Emmick, Jeffrey T.; Roeske, Roger W.; Tian, Zhenping; Ruest, Luc; Sutko, John L.

In: Journal of Medicinal Chemistry, Vol. 36, No. 10, 01.01.1993, p. 1319-1323.

Research output: Contribution to journalArticle

Gerzon, Koert ; Humerickhouse, Rod A. ; Besch, Henry R. ; Bidasee, Keshore R ; Emmick, Jeffrey T. ; Roeske, Roger W. ; Tian, Zhenping ; Ruest, Luc ; Sutko, John L. / Amino- and Guanidinoacylryanodines : Basic Ryanodine Esters with Enhanced Affinity for the Sarcoplasmic Reticulum Ca2+-Release Channel. In: Journal of Medicinal Chemistry. 1993 ; Vol. 36, No. 10. pp. 1319-1323.
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abstract = "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 Ca2+-release channel (SR CRC). In the presence of DCC and DMAP Cbz-β-alanine reacts with ryanodine in CH2C12 to give O10eq-Cbz-β-alanylryanodine (3a), which on hydrogenolysis yields the β-alanyl ester (4a). N,N′-bis-Cbz-S-methylthiourea reacts with 4a to yield β-N,N′-bis-Cbz-guanidinopropionylryanodine (5a). O10eq-β-guanidinopropionylryanodine (6a) is obtained on hydrogenolytic deprotection of 5a. The binding affinity of β-alanine ester (4a) and its glycyl congener (4b) is 2–3-fold greater, and that of the β-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.",
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AU - Gerzon, Koert

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AU - Besch, Henry R.

AU - Bidasee, Keshore R

AU - Emmick, Jeffrey T.

AU - Roeske, Roger W.

AU - Tian, Zhenping

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