title: Synthesis, QSAR and calcium channel modulator activity of new hexahydroquinoline derivatives containing nitroimidazole.
abstract: 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.
authors.affiliation: Medicinal & Natural Products Chemistry Research Centre, Shiraz University of Medical Sciences, Shiraz, Iran. mirir@sums.ac.ir
authors.forename: Ramin
authors.initials: R
authors.lastname: Miri
authors.forename: Katayoun
authors.initials: K
authors.lastname: Javidnia
authors.forename: Hossein
authors.initials: H
authors.lastname: Mirkhani
authors.forename: Bahram
authors.initials: B
authors.lastname: Hemmateenejad
authors.forename: Zahra
authors.initials: Z
authors.lastname: Sepeher
authors.forename: Masomeh
authors.initials: M
authors.lastname: Zalpour
authors.forename: Taherh
authors.initials: T
authors.lastname: Behzad
authors.forename: Mehdi
authors.initials: M
authors.lastname: Khoshneviszadeh
authors.forename: Najmeh
authors.initials: N
authors.lastname: Edraki
authors.forename: Ahmad R
authors.initials: AR
authors.lastname: Mehdipour
mesh_terms: 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
chemical_list: D015220:Calcium Channels; D009593:Nitroimidazoles; D011804:Quinolines