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J Biol Chem, Vol. 275, Issue 5, 3469-3478, February 4, 2000

Examining the Noncompetitive Antagonist-binding Site in the Ion Channel of the Nicotinic Acetylcholine Receptor in the Resting State^*

Michael P. Blanton^§, Elizabeth A. McCardy, and Martin J. Gallagher^¶

From the  Departments of Pharmacology and Anesthesiology, Texas Tech University Health Sciences Center, Lubbock, Texas 79430 and ^¶ Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110

3-Trifluoromethyl-3-(m-[¹²⁵I]iodophenyl)diazirine ([¹²⁵I]TID) has been shown to be a potent noncompetitive antagonist (NCA) of the nicotinic acetylcholine receptor (AChR). Amino acids that contribute to the binding site for [¹²⁵I]TID in the ion channel have been identified in both the resting and desensitized state of the AChR (White, B. H., and Cohen, J. B. (1992) J. Biol. Chem. 267, 15770-15783). To characterize further the structure of the NCA-binding site in the resting state channel, we have employed structural analogs of TID. The TID analogs were assessed by the following: 1) their ability to inhibit [¹²⁵I]TID photoincorporation into the resting state channel; 2) the pattern, agonist sensitivity, and NCA inhibition of [¹²⁵I]TID analog photoincorporation into AChR subunits. The addition of a primary alcohol group to TID has no demonstrable effect on the interaction of the compound with the resting state channel. However, conversion of the alcohol function to acetate, isobutyl acetate (TIDBIBA), or to trimethyl acetate leads to rightward shifts in the concentration-response curves for inhibition of [¹²⁵I]TID photoincorporation into the AChR channel and a progressive reduction in the agonist sensitivity of [¹²⁵I]TID analog photoincorporation into AChR subunits. Inhibition of [¹²⁵I]TID analog photoincorporation by NCAs (e.g. tetracaine) as well as identification of the sites of [¹²⁵I]TIDBIBA photoincorporation in the M2 segment indicate a common binding locus for each TID analog. We conclude that relatively small additions to TID progressively reduce its ability to interact with the NCA site in the resting state channel. A model of the NCA site and resting state channel is presented.

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