RT Journal Article
SR Electronic
T1 SR 33557, a novel calcium entry blocker. II. Interactions with 1,4-dihydropyridine, phenylalkylamine and benzothiazepine binding sites in rat heart sarcolemmal membranes.
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 600
OP 607
VO 255
IS 2
A1 P Nokin
A1 M Clinet
A1 P Beaufort
A1 L Meysmans
A1 R Laruel
A1 P Chatelain
YR 1990
UL http://jpet.aspetjournals.org/content/255/2/600.abstract
AB We have assessed the binding characteristics of a structurally novel calcium entry blocker, SR 33557, to purified rat heart sarcolemma. SR 33557 prevented completely the binding of (+)-[3H]PN200-110, (-)-[3H]D888 and cis-(+)-[3H]diltiazem to their specific binding sites in an apparently competitive manner (nH congruent to 1.0) and with a high affinity (Ki = 0.5-2.0 nM). Equilibrium and kinetic studies suggest that SR 33557 does not act as a simple competitive antagonist at the 1,4-dihydropyridine, the phenylalkylamine or the benzothiazepine-selective sites associated with the L-type calcium channel: 1) inhibition of (-)-[3H]D888 and cis-(+)-[3H]diltiazem binding by SR 33557 resulted in a decrease in maximum binding, 2) cis-(+)-diltiazem and (+)-PN200-110 allosterically increased the inhibition of (+)-[3H]PN200-110 binding and of (-)-[3H]D888 and cis-(+)-[3H]diltiazem binding by SR 33557, respectively and 3) dissociation kinetics of the three radioligands were accelerated by SR 33557. Calcium (in millimolar concentrations) decreased the apparent affinity of SR 33557 for its high-affinity binding sites. This observation was similar to that seen with the phenylalkylamines and cis-(+)-diltiazem, but contrasted from that seen with the 1,4-dihydropyridines. These results indicate that SR 33557 interacts with a high affinity to a novel binding site associated with the L-type calcium channel and has a strong negative allosteric interaction with the well-characterized binding sites for 1,4-dihydropyridines, phenylalkylamines and benzothiazepines.