Synthesis, QSAR and calcium channel modulator activity of new hexahydroquinoline derivatives containing nitroimidazole.
The discovery that 1,4-dihydropyridine class of calcium channel antagonists inhibit Ca2+ influx represented a major therapeutic advance in the treatment of cardiovascular disease. In contrast to the effects of known calcium channel blockers of the Nifedipine-type, the so-called calcium channel agonists, such as Bay K8644 and CGP 28392, increase calcium influx by binding at the same receptor regions. Our goal was to discover a dual cardioselective Ca2+-channel agonist/vascular selective smooth muscle Ca2+ channel antagonist third-generation 1,4-dihydropyridine drug which would have a suitable therapeutic profile for treating congestive heart failure (CHF) patients. A series of unsymmetrical alkyl, cycloalkyl and aryl ester analogues of 2-methyl-4-(1-methyl)-5-nitro-2-imidazolyl-5-oxo-1,4,5,6,7, 8-hexahydroquinolin-3-arboxylate were synthesized using modified Hantzsch reaction. All compounds show calcium antagonist activity on guinea-pig ileum longitudinal smooth muscle and some of them show agonist effect activity on guinea-pig auricle. Effect of structural parameters on the Ca2+ channel agonist/antagonist was evaluated by quantitative structure-activity relationship analysis. These compounds could be considered as a synthon for developing a suitable drug for treating CHF patients.
Miri
Ramin
R
Medicinal & Natural Products Chemistry Research Centre, Shiraz University of Medical Sciences, Shiraz, Iran. mirir@sums.ac.ir
Javidnia
Katayoun
K
Mirkhani
Hossein
H
Hemmateenejad
Bahram
B
Sepeher
Zahra
Z
Zalpour
Masomeh
M
Behzad
Taherh
T
Khoshneviszadeh
Mehdi
M
Edraki
Najmeh
N
Mehdipour
Ahmad R
AR
D000818:Animals; D015220:Calcium Channels / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D006168:Guinea Pigs; D006325:Heart Atria / Q000033:anatomy & histology / Q000187:drug effects; D006801:Humans; D007082:Ileum / Q000033:anatomy & histology / Q000187:drug effects; D008297:Male; D015394:Molecular Structure; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D009593:Nitroimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
D015220:Calcium Channels; D009593:Nitroimidazoles; D011804:Quinolines