CP-060S, (-)-(S)-2-[3,5-bis(1, 1-dimethylethyl)-4-hydroxyphenyl]-3-[3-[N-methyl-N-[2-(3, 4-methylenedioxyphenoxy)ethyl]amino]propyl]-1,3-thiazolidin- 4-one
hydrogen fumarate, is a novel cardioprotective
drug which is designed to prevent Ca2+ overload and cause vasorelaxation. The effects of this compound were evaluated and compared with those of CP-060R (enantiomer of
CP-060S,) and
diltiazem (Ca2+ channel antagonist) in a
veratridine-induced model of Ca2+ overload and vasorelaxation. After 5-min superfusion of
veratridine (74 microM), intracellular free
calcium concentrations ([Ca2+]i) of rat single cardiomyocytes, as measured with the
fura-2 procedure, were greatly elevated, from 44 +/- 5 nM to 3705 +/- 942 nM, and subsequently generated cell
contracture. Pretreatment of cardiomyocytes with more than 300 nM of
CP-060S or CP-060R for 30 min provided almost complete protection against the
veratridine-induced cell
contracture; in CP-060S(1 microM)-treated myocytes, [Ca2+]i were minimal and partially elevated from 42 +/- 5 nM to 72 +/- 14 nM after 5 min of
veratridine superfusion. In comparison,
diltiazem showed no protection below 1 microM and only partial protection
at 10 microM.
CP-060S, CP-060R and
diltiazem all shifted the concentration-response curve for CaCl2 to the right in a competitive manner in depolarized rat thoracic aorta. The pA2 values of
CP-060S, CP-060R and
diltiazem were 9.16 +/- 0.18, 8.24 +/- 0.14 and 7.66 +/- 0.09, respectively. Our results indicate that CP-060 behaves stereoselectively as a Ca2+ channel antagonist and non-stereo-selectively to protect against
veratridine-induced
contracture. The latter effect suggests that Ca2+ entry blockade is not the mechanism by which
CP-060S exerts cardioprotection.