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First published on December 9, 2005; DOI: 10.1124/mol.105.019257

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Received for publication September 26, 2005.
Revised December 9, 2005.
Accepted for publication December 9, 2005.

Evidence for a Multivalent Interaction of Symmetrical, N-Linked, Lidocaine Dimers with Voltage-Gated Na+ Channels

Jacqueline A. M. Smith 1*, Shanti M. Amagasu 2, Jeremy Hembrador 1, Sabine Axt 1, Ray Chang 1, Tim Church 1, Courtney Gee 1, John R. Jacobsen 1, Tom Jenkins 3, Elad Kaufman 1, Ngoc Mai 1, Ross G. Vickery 1

1 Theravance Inc 2 Theravance Inc. 3 Pharmacofore Inc

* Address correspondence to: E-mail: jsmith{at}theravance.com

Abstract

The interaction of symmetrical lidocaine dimers with voltage-gated Na+ channels (VGSCs) was examined using a FLIPR® membrane potential assay and voltage-clamp. The dimers, in which the tertiary amines of the lidocaine moieties are linked by an alkylene chain (2 to 6 methylene units), inhibited VGSC activator-evoked depolarization of cells heterologously-expressing rNav1.2a, hNav1.5 and rNav1.8, with potencies 10- to 100-fold higher than lidocaine (compound 1). The rank order of potency (C4 (compound 4) > C3 (compound 3) > C2 (compound 2) = C5 (compound 5) = C6 (compound 6) >> compound 1) was similar at each VGSC. Compound 4 exhibited strong use-dependent inhibition of hNav1.5 with pIC50 values < 4.5 and 6.0 for tonic and phasic block, respectively. Coincubation with local anesthetics, but not tetrodotoxin, attenuated compound 4-mediated inhibition of hNav1.5. These data suggest that the compound 4 binding-site(s) is identical, or allosterically-coupled, to the local anesthetic receptor. The dissociation rate of the dimers from hNav1.5 was dependent upon the linker length, with a rank order; compound 1>compound 5=compound 6>compound 2>>compound 3. The observation that both the potency and dissociation rate of the dimers was dependent upon linker length is consistent with a multivalent interaction at VGSCs. hNav1.5 VGSCs did not recover from inhibition by compound 4. However, 'chase' with free local anesthetic site inhibitors increased the rate of dissociation of compound 4. Collectively these data support the hypothesis that compound 4 simultaneously occupies two binding sites on VGSCs, both of which can be bound by known local anesthetic site inhibitors.


Key words: Sodium, Antiarrhythmic drugs, Local anesthetics


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