Dihidropiridin Türevlerinin Sentezi ve L-/T-Tipi Kalsiyum Kanal Bloke Edici Aktiviteleri

Abstract

1,4- Dihydropyridines (DHPs) are the most well known inhibitors of L-type calcium channels and have important therapeutic value against cardiovascular diseases. Since they target different calcium channel subtypes, they are also used in neurological and psychiatric diseases. When the derivatives that have been on the market for more than forty years are examined, it is obvious that the least modified part of the DHP ring is its fourth position. Within the scope of this thesis, twelve DHP-based hexahydroquinoline derivatives (DA1-DA12) were synthesized by focusing on the mentioned position of the ring. The synthesis of the compounds was carried out by the reaction of 4,4-dimethyl-1,3-cyclohexanedione, isobutyl acetoacetate, different aldehyde derivatives and ammonium acetate by applying the asymmetric Hantzsch reaction. The blocking percentages of L- (Cav1.2) and T- (Cav3.2) type calcium channels of the compounds, whose chemical structures were confirmed by 1H NMR, 13C NMR, mass spectrum and elemental analysis, were determined by patch clamp technique. Based on the results obtained, five compounds with different selectivity profiles were identified. The isomer separation of DA1, which selectively blocks the T-type calcium channel, was performed by HPLC, and the configuration of the enantiomers was determined by the vibrational circular dichroism method. The enantiomers were tested separately on Cav3.2 to determine which isomer was responsible for calcium channel inhibition. The binding mechanisms of the compounds to the calcium channels were investigated by homology modeling, docking and molecular dynamics simulation methods.