The pharmacology of novel acetylcholinesterase inhibitors, (+/-)-huprines Y and X, on the Torpedo electric organ

The effects of the tacrine-huperzine A. hybrid acetylcholinesterase inhibit ors, (+/-)-12-amino-3-chloro-9-methyl-6,7,10,11-tetrahydro-7,11-methanocycl oocta[b]quinoline hydrochloride ((+/-)-huprine Y) and (+/-)-12-amino-3-chlo ro-9-ethyl-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinoline hydrochlo ride ((+/-)-huprine X), were tested on spontaneous Synaptic activity by mea suring the amplitude, the rise time, the rate of rise, the half-width and t he area or the electrical charge of the miniature endplate potentials (m.e. p.ps) recorded extracellularly on Torpedo electric organ fragments. (+/-)-H uprine Y and (+/-)-huprine X at a concentration of 500 nM increased all the m.e.p.p. variables analyzed. The effect of (+/-)-huprine Y was smaller tha n that of (+/-)-huprine X for all the variables except for the rate of rise where there was no significant difference. The effects of these drugs were also tested on nicotinic receptors by analyzing the currents elicited by a cetylcholine (100 muM) in Xenopus laevis oocytes, transplanted with membran es from Torpedo electric organ. Both drugs inhibited the currents in a reve rsible manner, (+/-)-huprine Y (IC50 = 452 nM) being more effective than (/-)-huprine X (IC50 = 4865 nM). The Hill coefficient was 0.5 for both drugs . The inhibition of the nicotinic receptor was voltage-dependent and decrea sed at depolarizing potentials, and there was no significant difference in the effects between (+/-)-huprine Y and (+/-)-huprine X at concentrations n ear to their IC50 values. At depolarizing potentials between -20 and +15 mV , these drugs did not have any detectable effect on the blockade of the nic otinic receptor. Both huprines increased the desensitization of the nicotin ic receptors since the current closed quickly in the presence of the drugs, and there was no significant difference in this effect between (+/-)-hupri ne Y (500 nM) and (+/-)-huprine X (5 muM). We conclude that (+/-)-huprine Y and (+/-)-huprine X increase the level of acetylcholine in the synaptic cl eft more effectively than tacrine. The interaction of (+/-)-huprine X with nicotinic receptors is weaker than that of (+/-)-huprine Y, suggesting that (+/-)-huprine X would be more specific to maintain the extracellular acety lcholine concentration. (C) 2001 Elsevier Science B.V. All rights reserved.