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Updated: Oct 26, 2026

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Structure-Activity Relationships of 1,4-Benzodiazepines Inhibiting the Voltage-Gated Potassium Channel KV7.1
Florian Roßner1,2, Amy Methaq2, Guiscard Seebohm1,3
1GRK 2515, Chemical biology of ion channels (Chembion), Universität Münster, Münster, Germany.
Abstract:
KV7.1 antagonists hold potential for the treatment of diarrhea, reflux esophagitis, and hypoinsulinemia. The 1,4-benzodiazepine L768,673 ((R)-1) is a potent and selective KV7.1 channel blocker with a higher apparent affinity for the KV7.1 ion channel than other KV7.1 modulators including (R)-L3. In this study, L768,673 ((R)-1) was systematically modified at two positions, and the inhibitory effects of the resulting 1,4-benzodiazepines were evaluated by two-electrode voltage-clamp (TEVC) experiments. Acylation of the primary amines rac-7 and 9 provided amides 8 and 10a-e. Alkylation of secondary lactam 10a led to tertiary lactams 12a-c. Secondary lactams 10a-e and tertiary lactams 12a,b with large 1-substituents could not inhibit the KV7.1 channel. However, racemic 3-fluoropropyl derivative 12c was as active as the enantiomerically pure lead compound (R)-1 rendering 12c an interesting starting point for the development of an 18-fluorine labeled PET tracer.
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