Vol. 299, Issue 3, 1038-1048, December 2001

Local Anesthetics Noncompetitively Inhibit Function of Four Distinct Nicotinic Acetylcholine Receptor Subtypes

Cynthia L. Gentry and Ronald J. Lukas

Division of Neurobiology, Barrow Neurological Institute, Phoenix, Arizona and Committee on Neuroscience, University of Arizona, Tucson, Arizona

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 (1*-nAChR) or autonomic (34*-nAChR) nAChR, or heterologously expressed nAChR containing 4 with either 2- or 4-subunits (42- or 44-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 42-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.