Kondanse 1,4-Dihidropiridin Türevlerinin Sentezi ve L-/T-Tipi Kalsiyum Kanalları Üzerine Etkileri

Abstract

1,4-Dihydropyridines (DHPs) are crucial blockers of different calcium channel subtypes and have great therapeutic value against cardiovascular and neurophysiologic conditions. In this thesis, the design and the synthesis of sixteen DHP-based hexahydroquinoline derivatives as either selective or covalent inhibitors of calcium channels are reported. These compounds were achieved by the reaction of 4,4-dimethyl-1,3-cyclohexanedione, substituted salicylaldehyde, appropriate alkyl acetoacetate (benzyl acetoacetate or 2-(methacryloyloxy)ethyl acetoacetate) and ammonium acetate via modified Hantzsch reaction under microwave irradiation. The structures of the compounds were characterized by IR, 1H-NMR, 13C-NMR and mass spectra. Also, the proposed chemical structures of HM8 and HM12 were evaluated by X-ray analysis. The percentage of L- and T-type calcium channel current inhibition of the target compounds was determined by patch clamp technique. The obtained results showed that the covalent inhibitors of calcium channels could be achieved for the first time by introducing a Michael acceptor group into the ester side chain of the compounds. The proposed covalent binding between the compounds and the cysteine amino acid (Cys1492) within the DHP binding pocket of L-type calcium channel was supported by docking and pharmacophore analysis as well as a glutathione reactivity assay.