Hexahydroquinoline Featuring Amide Functionality: A Promising Scaffold With Calcium Channel Blocking Activity

Hexahydroquinoline (HHQ) is a widely recognized scaffold that has garnered considerable attention owing to its diverse pharmacological properties. The structure of HHQ includes a 1,4-dihydropyridine (DHP) ring, which serves as the pharmacophore for the predominant class of drugs known as calcium channel blockers. DHPs are frequently utilized in the management of cardiovascular diseases and also show potential for pain management. Since all DHPs on the market possess ester functionality, we aimed to employ bioisosteric replacement to observe if their amide-containing counterparts would still block calcium channels. Therefore, we synthesized new HHQs with ester or amide functionality (EM1-EM15) and investigated their effects on L-(Ca_v1.2) and T-(Ca_v3.2)-type calcium channels using the whole-cell patch clamp technique. Although the amide derivatives were somewhat less effective than their ester counterparts, they still blocked calcium channels to a significant degree. Retesting EM4 enantiomers on two types of calcium channels demonstrated that the (R)-isomer was more responsible for the blocking activity in both cases. Molecular docking and molecular dynamics simulations demonstrated that (R)-EM4 and (R)-EM6 adopt binding modes in Ca_v1.2 similar to amlodipine, while showing favorable stability. Docking studies in Ca_v3.2 suggested that EM compounds bind within the Ⅲ-Ⅳ fenestration, a reported non-selective DHP binding site. Furthermore, amide derivatives were found to be more metabolically stable based on the in vitro experiments conducted on rat microsomes. Overall, our study reveals HHQ with an amide group as a promising new scaffold for developing future calcium channel blockers for treating cardiovascular and pain conditions.