23 January 1997, Volume 120, Issue 3, Pages 429 – 438

Article

Activation and inhibition of rat neuronal nicotinic receptors by ABT-418 Roger L. Papke, 1,3, Jeffrey S. Thinschmidt2, Becky A. Moulton, 2, Edwin M. Meyer1 & Amy Poirier1 1Department of Pharmacology and Therapeutics, Box 100267 JHMHSC and      2Department of Neuroscience, Box 100244 JHMHSC, University of Florida, Gainesville, Florida 32610-0267, U.S.A.     3Author for correspondence

Keywords

ABT-418;   nicotinic AChR;   Xenopus oocytes;   epibatidine;   Alzheimer’s disease;   use-dependent inhibition

Abstract

1   ABT-418 appeared to function as a relatively broad spectrum activator of neuronal nicotinic receptors, expressed in Xenopus oocytes, with little cross reactivity to the mammalian muscle receptor subtype. However, the relative potencies of ABT-418 at the various subtypes differed from those acetylcholine (ACh). For example, ACh was most potent at 32 (EC5030 µM) and least potent at 22 (EC50500 µM). ABT-418 was most potent at 42 and 22 (EC506 µM and 11 µM, respectively) and least potent at 34 (EC50188 µM). 2   In addition to activating neuronal receptors, ABT-418 exhibited complex properties, including the inhibition of ACh responses. 3   The current responses elicited by relatively high concentrations of ABT-418 on the 42 receptor subtype were protracted beyond the application interval. The coapplication of ABT-418 with either of the use-dependent inhibitors bis(1,2,2,6,6-tetramethyl-4-pipendimyl)sebacate (BTMPS) or tetramethyl-pipenidine (TMP) eliminated the late protracted phase of the currents with only small effects on the initial activation phase. When the reversible inhibitor TMP was washed from the bath, the previously inhibited late current reappeared, suggesting that the observed mixed agonist-antagonist effects of ABT-418 and (±)-epibatidine on 42 were due to a concentration-dependent noncompetitive inhibition, an effect similar to that obtained for (-)-nicotine. 4   The inhibition of 42 receptors by ABT-418 was voltage-dependent. When high concentrations of ABT-418 were applied under depolarizing conditions, additional late currents could be observed under conditions which suggested that a build up of ABT-418 in an unstirred layer over the surface of the oocyte was occurring. This may have been due to the dissociation of the drug from channel blocking sites on the receptors themselves, or alternatively, from the plasma membrane of the cells.

Received 11 July, 96; Revised 14 October, 96; Accepted 25 October, 96

^© Macmillan Publishers Ltd 1997