Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 254, Issue -, Pages -Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2023.115353
Keywords
Pyrrolopyrimidine derivatives; Small conductance Ca2+-activated K+ channels; Positive modulator; Subtype selectivity; Spinocerebellar ataxias
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This article describes a new pyrrolopyrimidine derivative that selectively activates SK2-a channels and has the potential to cross the blood-brain barrier.
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 mu M) was identified with a similar to 5.4-fold higher potency on potentiating SK2-a channels at submicromolar concentrations as compared to NS13001 (EC50 = 1.83 +/- 0.50 mu M). 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.
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