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Allosteric interaction of trimebutine maleate with dihydropyridine binding sites

Time:2015/9/30 7:21:31

The effects of trimebutine maleate on [3H]nitrendipine binding to guinea-pig ileal smooth muscle membranes and Ca2(+)-induced contraction of the taenia cecum were studied. 

Specific binding of [3H]nitrendipine to smooth muscle membranes was saturable, with a KD value and maximum number of binding sites (Bmax) of 0.16 nM and 1070 fmol/mg protein, respectively. Trimebutine inhibited [3H]nitrendipine binding in a concentration-dependent manner with a Ki value of 9.3 microM. 

trimebutine maleate

In the presence of trimebutine (10 microM), Scatchard analysis indicated a competitive-like inhibition with a decrease in the binding affinity (0.31 nM) without a change in Bmax (1059 fmol/mg protein). However, a dissociation experiment using trimebutine (10 or 100 microM) showed that the decreased affinity was due to an increase of the dissociation rate constant of [3H]nitrendipine binding to the membrane. 

trimebutine maleate

In mechanical experiments using the taenia cecum, trimebutine (3-30 microM) caused a parallel rightward shift of the dose-response curve for the contractile response to a higher concentration range of Ca2+ under high-K+ conditions in a noncompetitive manner. These results suggest that trimebutine has negative allosteric interactions with 1,4-dihydropyridine binding sites on voltage-dependent Ca2+ channels and antagonizes Ca2+ influx, consequently inhibiting contractions of intestinal smooth muscle.