Local Anesthetics Noncompetitively Inhibit Function Of Four Distinct Nicotinic Acetylcholine Receptor Subtypes
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 (Î±1*-nAChR) or autonomic (Î±3Î²4*-nAChR) nAChR, or heterologously expressed nAChR containing Î±4 with either Î²2- or Î²4-subunits (Î±4Î²2- or Î±4Î²4-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 Î¼M) but lowest selectivity (âˆ¼4-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 Î¼M) and âˆ¼30-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 Î¼M and had only âˆ¼5-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 Î±4Î²2-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.
Journal of Pharmacology and Experimental Therapeutics
Gentry, Cynthia L. and Lukas, Ronald J., "Local Anesthetics Noncompetitively Inhibit Function Of Four Distinct Nicotinic Acetylcholine Receptor Subtypes" (2001). Translational Neuroscience. 244.