The <i>p</i>H-controlled antiarrhythmic action of dihydropyridines

Abstract

Investigations on the <i>ab initio </i>Hartree Fock molecular orbital calculations on Ca²⁺ channel blockers, in conjunction with intermolecular interaction calculations are reported here. The effect of substitution in the phenyl/pyridyl ring on the activity of the compound is discussed. The conformational mapping clearly indicates the differences in the disposition of phenyl ring with respect to the pyridyl ring. These differences lead to significant differences in terms of interactions with the Ca²⁺ ion and are able to explain the differences in the activity of <i>o-, m</i>-, and <i>p</i>-nifedipine. The Ca²⁺ ion holding capacity of the drugs has been investigated by drug-ion interaction energy calculations. The results indicate that the unprotonated form

of the drug is capable of blocking the channel by holding the ion on the essential side of the drug, while the protonated form is not capable of holding the Ca²⁺ ion. Depending on the state of protonation/unprotonation, a possible mechanism explaining use dependent blockade by DHP's has been suggested. The change in <i>p</i>H could result in change in state of protonation and thus o n/off interactions with the Ca²⁺ ion.