posted on 1996-06-07, 00:00authored byPhillip R. Jefferies, Peter J. Gengo, Michael J. Watson, John E. Casida
Ryanodine (1) and dehydroryanodine (2) are
equipotent probes for the ryanodine receptor
(ryr)
of calcium release channels and differ only in 9eq-methyl
for 1 and 9,21-methylene for 2.
Ryanoids 1 and 2 are used here to prepare
novel modifications of the cyclohexane substituents
to determine their effects on ryr activity and selectivity.
10-Oxo-1 when reacted with carbonyl
and other reagents gave 13 C-10 derivatives including the
epi-amine and epi-4-azidobenzoyl
hydrazide as a candidate affinity probe. Four derivatives of
2 included the Δ8-10-hydroxy and
Δ8-10-oxo compounds. Defunctionalization of the
cyclohexane ring of 2 or its 4,6-ethylboronate
was achieved in part by controlled periodate oxidation of the
9,21-diol to the 21-nor-9-oxo
compounds. These in turn provided access to the 9ax-
and 9eq-hydroxy derivatives and to the
21-nor-10-deoxy-9-oxo compound which was converted to
21-nor-10-deoxy-1 and 10-deoxy-2
along with the epimeric 10-deoxy-9-hydroxy compounds. Ryanoids of
similar potency to 1 as
inhibitors of [3H]-1 binding in mouse brain,
rabbit skeletal muscle, and canine ventricle
ryr
preparations and in a rat cardiac contractility assay (inhibition of
mechanical response to
electrical stimulation) are epi-1 and the
10-epi-amino, 10-epi-methoxyamino, and
10-epi-azidobenzoyl hydrazide derivatives and 10-deoxydehydroryanodine.
With a few exceptions the
potency of the ryanoids at the cardiac ryr correlates well
with their inhibition of cardiac
contractility, indicating that the activity is associated with
stabilizing the calcium release
channel in a subconducting state, thereby uncoupling the
excitation−contraction process.