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We have examined the effects of a number of derivatives of ryanodine on K+ conduction in the Ca2+ release channel purified from sheep cardiac sarcoplasmic reticulum (SR). In a fashion comparable to that of ryanodine, the addition of nanomolar to micromolar quantities to the cytoplasmic face (the exact amount depending on the derivative) causes the channel to enter a state of reduced conductance that has a high open probability. However, the amplitude of that reduced conductance state varies between the different derivatives. In symmetrical 210 mM K+, ryanodine leads to a conductance state with an amplitude of 56.8 +/- 0.5% of control, ryanodol leads to a level of 69.4 +/- 0.6%, ester A ryanodine modifies to one of 61.5 +/- 1.4%, 9,21-dehydroryanodine to one of 58.3 +/- 0.3%, 9 beta,21beta-epoxyryanodine to one of 56.8 +/- 0.8%, 9-hydroxy-21-azidoryanodine to one of 56.3 +/- 0.4%, 10-pyrroleryanodol to one of 52.2 +/- 1.0%, 3-epiryanodine to one of 42.9 +/- 0.7%, CBZ glycyl ryanodine to one of 29.4 +/- 1.0%, 21-p-nitrobenzoyl-amino-9-hydroxyryanodine to one of 26.1 +/- 0.5%, beta-alanyl ryanodine to one of 14.3 +/- 0.5%, and guanidino-propionyl ryanodine to one of 5.8 +/- 0.1% (chord conductance at +60 mV, +/- SEM). For the majority of the derivatives the effect is irreversible within the lifetime of a single-channel experiment (up to 1 h). However, for four of the derivatives, typified by ryanodol, the effect is reversible, with dwell times in the substate lasting tens of seconds to minutes. The effect caused by ryanodol is dependent on transmembrane voltage, with modification more likely to occur and lasting longer at +60 than at -60 mV holding potential. The addition of concentrations of ryanodol insufficient to cause modification does not lead to an increase in single-channel open probability, such as has been reported for ryanodine. At concentrations of > or = 500 mu M, ryanodine after initial rapid modification of the channel leads to irreversible closure, generally within a minute. In contrast, comparable concentrations of beta-alanyl ryanodine do not cause such a phenomenon after modification, even after prolonged periods of recording (>5 min). The implications of these results for the site(s) of interaction with the channel protein and mechanism of the action of ryanodine are discussed. Changes in the structure of ryanodine can lead to specific changes in the electrophysiological consequences of the interaction of the alkaloid with the sheep cardiac SR Ca2+ release channel.

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. Can. J. Chem. 59, 1105 (1981).Several isomeric compounds derived from the spiro systems 5 to 9 (Scheme 4) were obtained from the acid cyclization of the appropriate dihydroxy ketone precursor.The configuration and the conformation of the products obtained was determined by I3C nmr analysis and equilibration studies. The experimental results can be rationalized by taking into account the anomeric and the exo-anomeric effects and the usual steric interactions.PIERRE DESLONGCHAMPS, DARYL D. ROWAN, NORMAND POTHIER, TILLES SAUVE et JOHN K. SAUNDERS. Can. J. Chem. 59, 1105 (1981).Plusieurs composes isomeres derives des systemes spiranniques 5 a 9 (Schema 4) furent obtenus par cyclisation en milieu acide des precurseurs dihydroxycetoniques appropries.La configuration et la conformation des produits obtenus ont ete dkterminees par la rmn du I3C et par des etudes d'equilibration. Les resultats exptrimentaux sont expliques en tenant compte de I'effet anomere, de I'effet exo-anomtre et des interactions steriques habituelles.Stereoelectronic effects have been recognized for a long time to influence the configuration and the conformation of acetals, particularly in carbohydrates where these effects were first discovered and discussed in terms of the anomeric and exoanomeric effects (I).,,, a-And P-glycosides can theoretically take conformations A , , A,, A, and E,, E,, E, respectively (Scheme 1). The relative proportions of these various conformers in a and P-glycosides should be influenced by the usual steric interactions and by stereoelectronic effects. For instance, if stereoelectronic effects (anomeric and exo-anomeric effects) are important, the following predictions can be made: (a) conformer A, has only one anomeric effect and conformers A , and A, have two each,4 and since A, must be eliminated because of strong 'This work has been presented at the 8th Natural Products Symposium, University of West Indies, Mona, Jamaica, January 1980, and at the 1st International Symposium on Stereoelectronic Effects, University of St. Andrews, Scotland, July 1980.2The preference for an alkoxy group to be axially oriented is due to the anomeric effect, whereas the preference for the R group of the side chain at the anomeric center to be in the A , or the E, conformation in a and P-glycosides respectively is due to the exo-anomeric effect (Scheme 1).3The anomeric (or the exo-anomeric) effect is considered to be a stabilizing effect which occurs when an electron pair of an oxygen atom is oriented antiperiplanar to a C-OR bond. The stabilization would be gained through an electronic delocalization due to the overlap of an electron lone pair orbital of an oxygen with the antibonding orbital of a C-OR sigma bond (2, 3).41n this article, we use the term anomeric effect to describe either an anomeric or an exo-anomeric effect, assuming that both effects are of the same order of magnitude. steric interactions, A , must correspond to the most stable conformer of an a-glycoside; (b) conformer E, has no anomeric effect whereas El and E, have ...

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