Effects of T-588, a novel cognitive enhancer, on ADP-ribosylation of G(s alpha) by cholera toxin and cyclic AMP accumulation in rat cerebral cortex

We investigated the effects of R(-)-1-(benzo[b]thiophen-5-yl)-2-[2-(N,N-die thylamino)ethoxy]ethanol hydrochloride (T-588), a novel cognitive enhancer. on trimeric GTP-binding proteins (G proteins) and cyclic AMP accumulation in rat cerebral cortex. T-588 (0.1-1.0 mM) inhibited the ADP-ribosylation o f alpha subunit of G(s) in a concentration-dependent manner. Auto-ADP-ribos ylation of CTX was not inhibited by T-588. The stimulatory effect of guanos ine 5'-(3-O-thio)triphosphate (GTP gamma S) on CTX-catalyzed ADP-ribosylati on was attenuated by adding T-588 in assay mixture. ADP-ribosylation of G(i )G(o) by pertussis toxin was slightly inhibited by T-588. Isoproterenol-sti mulated cyclic AMP accumulation was inhibited by adding 3 mM T-588 to rat c erebral cortical slices. Next, we investigated the effects of isoproterenol and T-588 on GTP gamma S binding. Membranes were first incubated with or w ithout isoproterenol and T-588 in the presence of 0.2 mM GTP gamma S. then cholate extract preparations were prepared from the washed membranes. Inter estingly, the [P-32]ADP-ribosylation of G(s alpha) was enhanced not only by isoproterenol but also by T-588. Although the obtained results are apparen tly inconsistent, T-588 seems to interact with G proteins, specifically G(s ). (C) 1999 Elsevier Science Ltd. All rights reserved.