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1,4-Diazabicyclo[2.2.2]octane Derivatives: A Novel Class of Voltage-Gated Potassium Channel Blockers

Greenberg Division of Cardiology, Department of Medicine and Department of Pharmacology, Weill Medical College, Cornell University, New York, New York (E.G., G.W.A.); Department of Chemistry and Physical Science, Pace University, New York, New York (J.-L.C.); and Department of Chemistry and Biochemistry, Queens College of the City University of New York, Flushing, New York (R.E.)

Voltage-gated potassium (Kv) channels are targets for therapeutic drugs in the treatment of pathologic conditions including cardiac arrhythmia and epilepsy. In this study, we synthesized three classes of novel polyammonium compounds incorporating the bicyclic unit 1,4-diazabicyclo[2.2.2]octane (DABCO) and tested their action on three representative mammalian Kv channels (Kv2.1, Kv3.4, and Kv4.2) expressed in Xenopus laevis oocytes. Nonsubstituted DABCO did not block the Kv channels tested. Simple DABCO monostrings and diDABCO strings inhibited Kv2.1 and Kv3.4 channels, with potency increasing with string length for both these DABCO classes. Both Kv2.1 and Kv3.4 were most sensitive to C₁₆ monostrings, with IC₅₀ values of 1.9 and 0.6 µM, respectively. For compounds comprising two DABCO groups separated by an aromatic ring, inhibition depended upon relative positioning of the two DABCO groups, and only the para form (JC638.2) was active, blocking Kv2.1 with an IC₅₀ of 186 µM. Kv4.2 channels were relatively insensitive to all compounds tested. Unlike the tetraethylammonium ion (TEA), neither JC638.2 nor C₁₆ monostring TA279 produced block when applied intracellularly via the recording electrode to Kv2.1 channels expressed in Chinese hamster ovary cells, suggesting against an internal site of action. However, JC638.2 protected an introduced cysteine (K356C) in the Kv2.1 outer pore from permanent modification by methanethiosulfonate ethyltrimethylammonium (MTSET). These data suggest that JC638.2 occupies an external binding site similar to that of TEA in the Kv2.1 outer pore, but with much higher affinity than TEA. These DABCO salts represent a new class of Kv channel blockers, some with higher potencies than any previously described quaternary ammonium ions. The potential for synthesis of an array of modular derivatives suggests that DABCO compounds hold promise as probes of Kv channel structure and identity and as potential therapeutic agents.

Address correspondence to: Dr. Geoffrey W. Abbott, Starr 463, Greenberg Division of Cardiology, Weill Medical College of Cornell University, 520 East 70th Street, New York, NY 10021. E-mail: gwa2001{at}med.cornell.edu