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

Theravance Inc., South San Francisco, California

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 (two to six methylene units), inhibited VGSC activator-evoked depolarization of cells heterologously-expressing rat (r) Na_v1.2a, human (h) Na_v1.5, and rNa_v1.8, 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 hNa_v1.5 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 hNa_v1.5. 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 hNa_v1.5 was dependent upon the linker length, with a rank order of 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. hNa_v1.5 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. Together, 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.

Address correspondence to: Jacqueline Smith, Theravance Inc., 901 Gateway Blvd., South San Francisco, CA 94080. E-mail: jsmith{at}theravance.com

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