Focusing on C-4 position of Hantzsch 1,4-dihydropyridines: Molecular modifications, enantioseparation, and binding mechanism to L- and T-type calcium channels

Akman D., Denzinger K., Huang S., Lee J., Nafie J. W., Wolber G., ...More

European Journal of Medicinal Chemistry, vol.244, 2022 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 244
  • Publication Date: 2022
  • Doi Number: 10.1016/j.ejmech.2022.114787
  • Journal Name: European Journal of Medicinal Chemistry
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, CAB Abstracts, Chemical Abstracts Core, Chimica, EMBASE, MEDLINE, Veterinary Science Database
  • Keywords: Hantzsch synthesis, Hexahydroquinoline, Chiral center, Patch clamp, Molecular dynamics, 3D pharmacophore
  • Hacettepe University Affiliated: Yes


© 2022 Elsevier Masson SAS1,4-Dihydropyridines (DHPs) represent the blockbuster class of L-type calcium channel blockers that have tremendous therapeutic value against cardiovascular conditions. Due to their abilities to additionally target other subtypes of calcium channels, DHPs are also considered promising molecules for the treatment of neurological and psychiatric disorders. Having been in the market for more than forty years, DHP is one of the most modified scaffolds for the development of novel molecules acting on calcium channels. Taking the chemical structures of approved DHPs into account, it is noteworthy that C-4 position is the least modified part of the ring system. Therefore, in the present study, we focused on this location and carried out various molecular modifications to obtain twelve potential calcium channel blockers with a DHP-based hexahydroquinoline scaffold (DA1-DA12). The whole-cell patch clamp technique applied to analyze the blocking ability of the synthesized compounds on both L- (Cav1.2) and T- (Cav3.2) type calcium channels revealed five blockers with different selectivity profiles. Introducing naphthyl moiety onto the C-4 position of the main scaffold led to the identification of a selective blocker of Cav1.2 (DA8). The benzodioxole-substituted derivative (DA1) was the most potent and selective Cav3.2 inhibitor, therefore, its enantiomers were separated using HPLC on a chiral stationary phase. Retesting single isomers on Cav3.2 revealed that S-enantiomer was mainly responsible for the block. Finally, DA compounds were docked into two generated homology models of L- and T-type calcium channels. Molecular dynamics (MD) simulations and 3D pharmacophore modeling provided further insights into the detailed binding mechanism of DHPs to Cav1.2 as well as to Cav3.2.