A novel dihydropyridine with 3-aryl meta-hydroxyl substitution blocks L-type calcium channels in rat cardiomyocytes.
BACKGROUND
Dihydropyridines are widely used for the treatment of several cardiac diseases due to their blocking activity on L-type Ca(2+) channels and their renowned antioxidant properties.


METHODS
We synthesized six novel dihydropyridine molecules and performed docking studies on the binding site of the L-type Ca(2+) channel. We used biochemical techniques on isolated adult rat cardiomyocytes to assess the efficacy of these molecules on their Ca(2+) channel-blocking activity and antioxidant properties. The Ca(2+) 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.


RESULTS
Our docking studies show that a novel compound with 3-OH substitution inserts into the active binding site of the L-type Ca(2+) 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 Ca(2+) channel as opposed to para-substituted compounds. In the tests we performed, none of the molecules showed antioxidant properties.


CONCLUSIONS
Only 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.
Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad Medicina, Universidad de Chile, Santiago, Chile; Centro Estudios Moleculares de la Célula (CEMC), Facultad de Ciencias Químicas y Farmacéuticas & Facultad Medicina, Universidad de Chile, Santiago, Chile.
David
D
Galvis-Pareja
Departamento de Química Inorgánica y Analítica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile.
Gerald
G
Zapata-Torres
Centro Estudios Moleculares de la Célula (CEMC), Facultad de Ciencias Químicas y Farmacéuticas & Facultad Medicina, Universidad de Chile, Santiago, Chile; Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
Jorge
J
Hidalgo
Centro Estudios Moleculares de la Célula (CEMC), Facultad de Ciencias Químicas y Farmacéuticas & Facultad Medicina, Universidad de Chile, Santiago, Chile.
Pedro
P
Ayala
Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad Medicina, Universidad de Chile, Santiago, Chile; Centro Estudios Moleculares de la Célula (CEMC), Facultad de Ciencias Químicas y Farmacéuticas & Facultad Medicina, Universidad de Chile, Santiago, Chile; Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
Zully
Z
Pedrozo
Centro Estudios Moleculares de la Célula (CEMC), Facultad de Ciencias Químicas y Farmacéuticas & Facultad Medicina, Universidad de Chile, Santiago, Chile; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden; Cardiovascular and Metabolic Diseases iMed, AstraZeneca R&D, 43183 Mölndal, Sweden.
Cristián
C
Ibarra
Cardiovascular and Metabolic Diseases iMed, AstraZeneca R&D, 43183 Mölndal, Sweden.
Guillermo
G
Diaz-Araya
The Hatter Cardiovascular Institute, University College London, London, UK.
Andrew R
AR
Hall
Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad Medicina, Universidad de Chile, Santiago, Chile; The Hatter Cardiovascular Institute, University College London, London, UK.
Jose Miguel
JM
Vicencio
Departamento de Química Farmacológica y Toxicológica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile.
Luis
L
Nuñez-Vergara
Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad Medicina, Universidad de Chile, Santiago, Chile; Centro Estudios Moleculares de la Célula (CEMC), Facultad de Ciencias Químicas y Farmacéuticas & Facultad Medicina, Universidad de Chile, Santiago, Chile; Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile; Department of Internal Medicine/Cardiology Division, University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address: slavander@uchile.cl.
Sergio
S
Lavandero
D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects*; D002316:Cardiotonic Agents / Q000494:pharmacology; D002469:Cell Separation; D002470:Cell Survival / Q000187:drug effects; D004095:Dihydropyridines / Q000737:chemistry / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D006900:Hydroxylation; D008297:Male; D008958:Models, Molecular; D032383:Myocytes, Cardiac / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D002316:Cardiotonic Agents; D004095:Dihydropyridines; D017382:Reactive Oxygen Species; D002118:Calcium
Calcium; Cardiomyocytes; Dihydropyridine; Heart; L-type calcium channels