Effects of CI-1002 and CI-1017 on spontaneous synaptic activity and on the nicotinic acetylcholine receptor of Torpedo electric organ

Abstract

The effect of azepino[2,1- b]quinazoline 1,3-dichloro-6,7,8,9,10,12-hexahydro-, mono-hydrochloride (CI-1002), a tacrine derivative, and 1-azabicyclo[2.2.1]heptan-3-one, O-[3-(methoxyphenyl)-2-propynyl]oxime [ R-( Z)]-2-butenedioate (CI-1017), a muscarinic M 1 receptor agonist, on spontaneous synaptic activity was investigated by measuring amplitude, rise time, velocity of rising, half-width, and electrical charge of miniature endplate potentials (m.e.p.p.) recorded extracellularly in Torpedo electric organ fragments. The effect of CI-1002 and CI-1017 on the nicotinic acetylcholine receptor was investigated by measuring the current induced by acetylcholine in Xenopus laevis oocytes transplanted with membranes from Torpedo electric organ. CI-1002, at a concentration of 1 μM, altered the m.e.p.p. by increasing the amplitude (from 1.08±0.01 to 2.76±0.03 mV), rise time (from 0.700±0.006 to 1.02±0.01 ms), rising rate (from 1.79±0.02 to 3.45±0.05 mV/ms), half-width (from 0.990±0.008 to 2.40±0.02 ms), and electrical charge (from 304±4 to 784±11 mV s). CI-1017, at a concentration of 1 μM, altered the m.e.p.p. by decreasing the amplitude (from 1.08±0.01 to 0.650±0.007 mV), rise time (from 0.700±0.006 to 0.530±0.007 ms), rising rate (from 1.79±0.02 to 1.53±0.02 mV/ms), half-width (from 0.990±0.008 to 0.670±0.007 ms), and electrical charge (from 304±4 to 75±1 mV s). CI-1002 inhibited the acetylcholine-induced current of nicotinic acetylcholine receptors with an IC 50 of 3.4±0.3 μM. CI-1017 inhibited the acetylcholine-induced current of nicotinic acetylcholine receptors with an IC 50 of 0.8±0.1 μM. These results indicate that, although both drugs interacted negatively with nicotinic acetylcholine receptors, CI-1002 overcame this inhibition by recruiting more acetylcholine to build a quantum.