Design, Synthesis and Bioactivity of [3.3.3]Propellane-Based Voltage-Gated Calcium Channel alpha 2 delta Subunit Ligands

Voltage-gated calcium channel (VGCC) alpha 2 delta subunit ligands represent one of the most efficacious and safest classes of drugs for the treatment of chronic neuropathic pain. In order to investigate the effect of the sterically bulky alkyl moieties with constrained conformation on the bioactivity of VGCC alpha 2 delta subunit ligands, three.-aminobutyric acids (GABAs) substitued with [3.3.3]propellane and one GABA with bicyclo[3.3.0]octane were designed and synthesized. All the syntheszied compounds were characterzied by H-1 NMR, C-13 NMR and high-resolution mass spectrometry (HRMS), and subjected to in vitro human VGCC alpha 2 delta subunit binding assay. The bioactivity results indicated that: [3.3.3]propellane can be tolerated in the VGCC alpha 2 delta ligand, but its size is bulkier than the optimal size. The amino group in GABA chain can not be modified or replaced; otherwise, the bioactivity will decrease dramatically or even be lost. The structure-activity relationship revealed in the present study may be helpful for the future design of novel VGCC alpha 2 delta subunit ligands.

Automated summary

Voltage-gated calcium channel (VGCC) alpha 2 delta subunit ligands are highly effective and safe drugs for chronic neuropathic pain. In this study, bulky alkyl moieties with constrained conformation were designed and synthesized to investigate their effect on the bioactivity of VGCC alpha 2 delta subunit ligands. The results showed that [3.3.3]propellane is tolerated but bulkier than optimal size, and modification or replacement of the amino group in GABA chain significantly decreases or eliminates the bioactivity. The structure-activity relationship revealed in this study may aid in the design of novel VGCC alpha 2 delta subunit ligands.