Abstract

Local anesthetics (LAs) are considered to act primarily by inhibiting voltage-gated Na⁺ channels. However, LAs also are pharmacologically active at other ion channels including nicotinic acetylcholine receptors (nAChR). nAChR exist as a family of diverse subtypes, each of which has a unique pharmacological profile. The current studies established effects of LAs on function of four human nAChR subtypes: naturally expressed muscle-type (α1*-nAChR) or autonomic (α3β4*-nAChR) nAChR, or heterologously expressed nAChR containing α4 with either β2- or β4-subunits (α4β2- or α4β4-nAChR). Of the LAs tested, those with structures containing two separated aromatic rings (e.g., proadifen and adiphenine) had the greatest inhibition potency (IC₅₀ values between 0.34 and 6.3 μM) but lowest selectivity (∼4-fold) across the four nAChR subtypes examined. From the fused, two-ring (isoquinoline backbone) class of LAs, dimethisoquin had comparatively moderate inhibition potency (IC₅₀ values between 2.4 and 61 μM) and ∼30-fold selectivity across nAChR subtypes. Lidocaine, a commonly used LA from the single ring category of LAs, blocked nAChR function with IC₅₀ values of between 52 and 250 μM and had only ∼5-fold selectivity across nAChR subtypes. Its quaternary triethyl ammonium analog, QX-314, had greater inhibition potency, but the trimethyl ammonium derivative, QX-222, was the least potent LA at all but the α4β2-nAChR subtype. With only a few exceptions, LA effects were consistent with noncompetitive inhibition of nAChR function and occurred at therapeutic doses. These studies suggest structural determinants for LA action at diverse nAChR subtypes and that nAChR likely are clinically relevant targets of LAs.