1,4-Dihydropyridine (DHP), an important class of calcium antagonist, inhibits the influx of extracellular Ca+2 through L-type voltage-dependent calcium channels. Three-dimensional (3D) structure of calcium channel as a receptor for 1,4-dihydropyridine is a step in understanding its mode of action. Protein structure prediction and modeling tools are becoming integral parts of the standard toolkit in biological and biomedical research. So, homology modeling (HM) of calcium channel alpha-1C subunit as DHP receptor model was achieved. The 3D structure of potassium channel was used as template for HM process. The resulted dihydropyridine receptor model was checked by different means to assure stereochemical quality and structural integrity of the model. This model was achieved in an attempt to understand the mode of action of DHP calcium channel antagonist and in further computer-aided drug design (CADD) analysis. Also the structure-activity relationship (SAR) of DHPs as antihypertensive and antianginal agents was reviewed, summarized, and discussed. 1. Introduction Voltage-gated calcium channels play an integral role in the entry of Ca2+ ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division, and cell death [1, 2]. The isoform alpha-1C gives rise to long-lasting (L-type) calcium currents. They are blocked by 1,4-dihydropyridines (DHPs) such as nifedipine, phenylalkylamines such as verapamil, and benzothiazepines such as diltiazem [3]. Voltage-dependent calcium channels are multisubunit complexes, consisting of alpha-1, alpha-2, beta, and delta subunits in a 1？:？1？:？1？:？1 ratio. The channel activity is directed by the pore-forming and voltage-sensitive alpha-1 subunit. In many cases, this subunit is sufficient to generate voltage-sensitive calcium channel activity that displays the major electrophysiological and pharmacological properties of the full-fledged heteromeric channels [4–7]. DHP is the most feasible heterocyclic ring with various substitutions at several positions [8]. The discovery that the 1,4-dihydropyridine class of calcium channel blockers inhibits the Ca2+ influx represents a major therapeutic advance in the treatment of cardiovascular diseases, such as hypertension, angina pectoris, and other spastic smooth muscle diseases [9]. The most feasible position for substitution is the 4-position which exhibits various calcium channel antagonist activities [10] and the heterocyclic ring is the common
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