Use of Dabco-Based Compounds as Potassium Channel Blockers and Openers

Invention

• Novel small molecules based on DABCO
• Methods to use these molecules to modulate ion channels, especially potassium channels.

Geoffrey Abbott (Weill Cornell Medicine Department of Medicine), Robert Engel (Queens College of CUNY Department of Chemistry & Biochemistry), and JaimeLee Cohen (Pace University's Department of Chemistry and Physical Sciences), have collaborated to develop novel analogs of DABCO (the bicyclic molecule 1,4 diazabicyclo[2.2.2]octane), and methods to use them to modulate ion channels.

Professors Engel and Cohen are experts in the synthesis and use of DABCO, and have developed several analogs and uses for them, including their use in antimicrobial fabric coatings.

Professor Abbott noticed that DABCO is similar in structure to the quaternary ammonium ion tetraethylammonium (TEA), which has been widely used to block and thus distinguish certain ion currents in vivo.

The inventors synthesized several classes of novel polyammonium compounds incorporating DABCO and tested their action on mammalian ion channels.

With respect to the potassium channels Kv2.1 and Kv3.4, the potency of the analogs increases with chain length for compounds with a hydrocarbon tail linked to DABCO (monostring) and also in compounds with two DABCO moieties linked by a hydrocarbon tail (diDABCO); Kv2.1 shows an IC50 of 1.9 uM for the C16 monostring, indicating 3,000-fold higher sensitivity than for TEA. For compounds in which two DABCO moieties are separated by an aromatic ring, inhibition is critically dependent upon relative positioning of the two DABCO groups.

DABCO compounds represent a new class of Kv channel blockers with varying degrees of potency and specificity. The potential for synthesis of an array of modular derivatives suggests that DABCO compounds hold promise as potential therapeutic agents in cardiovascular diseases and conditions, immune system diseases and conditions, smooth muscle disorders, central and peripheral nervous system diseases and disorders - including pain, skeletal muscle diseases and disorders, endocrine disorders (e.g., disorders associated with hormone secretion), and cell proliferative disorders, and degenerative disorders.

We have in vivo data showing that one of our compounds has efficacy in an animal model of epilepsy – the data are unpublished but are available under confidentiality.