A novel dihydropyridine with 3-aryl meta-hydroxyl substitution blocks L-type calcium channels in rat cardiomyocytes

• Dihydropyridine (DHP) molecules are widely used in cardiovascular disease.
• DHPs block Ca2 + entry through LTCC—some DHPs have antioxidant activity as well.
• We synthesized 6 new DHPs and tested their Ca2 + blocking and antioxidant activities.
• 3-Aryl meta-hydroxyl substitution strongly increases their Ca2 + blocking activity.
• 3-Aryl meta-hydroxyl substitution did not affect the antioxidant properties.

RationaleDihydropyridines are widely used for the treatment of several cardiac diseases due to their blocking activity on L-type Ca2 + channels and their renowned antioxidant properties.MethodsWe synthesized six novel dihydropyridine molecules and performed docking studies on the binding site of the L-type Ca2 + channel. We used biochemical techniques on isolated adult rat cardiomyocytes to assess the efficacy of these molecules on their Ca2 + channel-blocking activity and antioxidant properties. The Ca2 + channel-blocking activity was evaluated by confocal microscopy on fluo-3AM loaded cardiomyocytes, as well as using patch clamp experiments. Antioxidant properties were evaluated by flow cytometry using the ROS sensitive dye 1,2,3 DHR.ResultsOur docking studies show that a novel compound with 3-OH substitution inserts into the active binding site of the L-type Ca2 + channel previously described for nitrendipine. In biochemical assays, the novel meta-OH group in the aryl in C4 showed a high blocking effect on L-type Ca2 + channel as opposed to para-substituted compounds. In the tests we performed, none of the molecules showed antioxidant properties.ConclusionsOnly substitutions in C2, C3 and C5 of the aryl ring render dihydropyridine compounds with the capacity of blocking LTCC. Based on our docking studies, we postulate that the antioxidant activity requires a larger group than the meta-OH substitution in C2, C3 or C5 of the dihydropyridine ring.