ACTIVATION AND INHIBITION OF RAT NEURONAL NICOTINIC RECEPTORS BY ABT-418

1 ABT-418 appeared to function as a relatively broad spectrum activato r of neuronal nicotinic receptors, expressed in Xenopus oocytes, with little cross reactivity to the mammalian muscle receptor subtype. Howe ver, the relative potencies of ABT-418 at the various subtypes differe d from those acetylcholine (ACh). For example, ACh was most potent at alpha 3 beta 2 (EC(50)approximate to 30 mu M) and least potent at alph a 2 beta 2 (EC(50)approximate to 500 mu M). ABT-418 was most potent at alpha 4 beta 2 and alpha 2 beta 2 (EC(50)approximate to 6 mu M and 11 mu M, respectively) and least potent at alpha 3 beta 4 (EC(50)approxi mate to 188 mu M). 2 In addition to activating neuronal receptors, ABT -418 exhibited complex properties, including the inhibition of ACh res ponses. 3 The current responses elicited by relatively high concentrat ions of ABT-418 on the alpha 4 beta 2 receptor subtype were protracted beyond the application interval. The coapplication of ABT-418 with ei ther of the use-dependent inhibitors bis(1,2,2,6,6-tetramethyl-4-pipen dimyl)sebacate (BTMPS) or tetramethylpipenidine (TMP) eliminated the l ate protracted phase of the currents with only small effects on the in itial activation phase. When the reversible inhibitor TMP was washed f rom the bath, the previously inhibited late current reappeared, sugges ting that the observed mixed agonist-antagonist effects of ABT-418 and (+/-)-epibatidine on alpha(4) beta 2 were due to a concentration-depe ndent noncompetitive inhibition, an effect similar to that obtained fo r (-)-nicotine. 4 The inhibition of alpha 4 beta 2 receptors by ABT-41 8 was voltage-dependent. When high concentrations of ABT-418 were appl ied under depolarizing conditions, additional late currents could be o bserved 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 blocki ng sites on the receptors themselves, or alternatively, from the plasm a membrane of the cells.