Design, synthesis and biological evaluation of pyrrolopyrimidine derivatives as novel and selective positive modulator of the small conductance Ca2+-activated K+ channels

Abstract

The type 2 small conductance Ca²⁺-activated K⁺ channels (SK2) have been considered as one of the most promising therapeutic targets for spinocerebellar ataxias type 2 (SCA2) by playing a critical role in the control of normal purkinje cells (PCs) pacemaking. Herein, a novel series of pyrrolopyrimidine derivatives were designed and synthesized from the lead compound NS13001 as subtype-selective modulators of SK channels. Among them, the halogen-substituted compound 12b (EC₅₀ = 0.34 ± 0.044 μM) was identified with a ∼5.4-fold higher potency on potentiating SK2-a channels at submicromolar concentrations as compared to NS13001 (EC₅₀ = 1.83 ± 0.50 μM). Furthermore, compound 12b exhibited selectivity on SK2-a/SK3 subtype by displaying 93.33 ± 3.26% efficacies on SK2-a channels, and 84.54% ± 7.49% on SK3 channels. In addition, compound 12b demonstrated the potential to cross the blood-brain barrier (BBB) with suitable pharmacokinetic properties and low cytotoxicity. Molecular docking study also unveiled the binding interactions of compound 12b with SK2-CaM protein complex. Overall, the novel pyrrolopyrimidines provide an insightful guidance for future structural optimization of SK channel agonists.

Keywords: Positive modulator; Pyrrolopyrimidine derivatives; Small conductance Ca(2+)-activated K(+) channels; Spinocerebellar ataxias; Subtype selectivity.