Facilitation of calcium-dependent cholinergic function by ucb L059, a new "second generation" nootropic agent

We have investigated the effect of piracetam (PIR) and of its structural analogs, ucb L059 and ucb L060, the optical isomer of ucb L059, on cholinergic function in the guinea pig ileum in vitro. Only ucb L059 (10 microM-10 mM) caused contraction of the ileal preparation in a dose-dependent manner. This effect was inhibited by atropine (greater than or equal to 3.2 nM), by tetrodotoxin (10 nM) and by a combined treatment of veratridine (50 nM) and hemicholinium-3 (HC-3;0.5 mM), and was potentiated by physostigmine (50 nM). Electrically evoked contractions (EEC) of guinea pig ileal preparations subjected to HC-3 (0.5 mM) followed by veratridine (50 microM) were suppressed due to depletion of acetylcholine. Choline (greater than or equal to 3.2 10(-7)M) and ucb L059 (0.1-10 mM), but not ucb L060, facilitated recovery of EEC in a dose-dependent manner. This effect was abolished by HC-3. In addition, twitch recovery was inversely related to the concentration of Ca+2 in the medium. These results indicate that ucb L059, a close structural analog of piracetam, appears to facilitate cholinergic function in vitro through a stereospecific mechanism.