Question

2. Outline essential structural features a 1,4-Dihydropyridine must possess for effective Ca2+ channel blocking capability. Why are dimethyl 1,4-Dihydro-2,6-Dimethylpyridine-3,5-Dicarboxylate and diethyl 1,4-Dihydro-2,6-Dimethylpyridine-3,5-Dicarboxylate ineffective in this regard?

Answer 1

1,4-Dihydropyridine (DHP), an important class of calcium antagonist, inhibits the influx of extracellular Ca+2 through L-type voltage-dependent calcium channels. Generally speaking, DHPs can be prepared via the Hantzsch methodology, reduction of or addition to appropriate pyridines and several cycloaddition reactions.The presence of 1,4-DHP ring, as an essential moiety for calcium antagonist activity, has been assured in many literatures. This important class of calcium channel antagonists has been proven to act by decreasing the passage of the transmembrane calcium current on binding, causing a long lasting relaxation in smooth muscle and reduction of
contractility throughout the cardiac muscle.

Some investigations revealed that dihydropyrimidine ring could be used in place of 1,4-DHP ring. Both 1,4-DHP and dihydropyrimidine rings adopt boat conformation with hydrogen atom attached to Sp3-hybridized nitrogen. Ring oxidation or N1 substitution abolishes activity. Oxidation of the ring, protonation of N1, or substitution at this position changes boat conformation and the position of hydrogen bonding. So, this hydrogen atom is involved in a direct interaction with the receptor result in no binding with DHP. Substitution at 2,6-positions of 1,4-DHP ring should be lower alkyl group. however, recent studies revealed that one bulky group like phenyl group at C-6 position increased activity and selectivity due to its interaction with high lipophilic pocket in the receptor. These lipophilic aromatic substituents attached to the C-6 position of 1,4- DHP ring are supposed to improve penetration into organs; these compounds are more active as compared with similar compounds that contain methyl moiety in C-6 position. This observation of decreasing activity is in contrast to the effect of increasing lipophilicity.This is due to the increase in steric hindrance by phenyl group. So, there is a challenge to make a suitable balance between lipophilicity and steric hindrance for the calcium channel antagonist activity of DHPs.

Compounds with ortho- or meta-substitution of electron-withdrawing nature possess optimum activity, while para-substitution shows decrease in activity according to its electronic and steric effect. The importance of the ortho- and meta-substituents is to “lock” the conformation of the 1,4-DHP such that the C-4 position aromatic ring is perpendicular to the 1,4- DHP ring. This perpendicular conformation has been proposed to be essential for the activity of the 1,4-DHPs.

From the above discussions, the 1,4-DHPs structure has two axes: affinity axis and chirality-activity axis (below Figure). Affinity axis is in charge of binding to the receptor and consists of N-H group and C-4 position aromatic substitution. Chirality-activity axis is composed of the two ester functional groups of substituents at C-3 and C-5 positions of the DHP ring. It is responsible for distinguishing the activity, agonist and antagonist, and also enantiomeric selectivity; that is, some enantiomers are more active than the others. The two axes are cross not parallel.