Cognition enhancement by the acetylcholine releaser DuP 996

Abstract

Cook, L., V.J. Nickolson, G.F. Steinfels, K.W. Rohrbach, and V.J. DeNoble: Cognition enhancement by the acetylcholine releaser DuP 996. Drug Dev. Res. 19:301-314, 1990.DuP 996, 3,3-Bis(4-pyridinylmethyl)-l -phenylindolin-2-one, a potent in vitro and in vivo releaser of acetylcholine (ACh), dopamine (DA), and serotonin (5HT) in rat brain, significantly enhanced the performance of rats and mice in several behavioral test procedures. At doses of 0.01-0.1 mgikg S.C. DuP 996 protected against a hypoxia-induced passive avoidance deficit in rats. In active avoidance procedures, DuP 996 enhanced acquisition of responses: in rats, at doses between 0.085 and 0.85 mgikg S.C. and 0.25 and 0.85 mgikg p.0.; in mice, at doses between 0.85 and 2.5 mgikg S.C. These effects occurred without any alteration of sensitivity to foot-shock. In addition, DuP 996 prevented a C0,-induced retention deficit of a passive avoidance response when administered prior to acquisition testing.In a test for acquisition of lever pressing for food in the rat, DuP 996 increased the proportion of animals acquiring this response. Thus, DuP 996 was active in both the shock-and appetitive-motivated procedures and was shown to enhance performance levels when administered post-training as well as before training trials. These results suggest that DuP 996 may be useful in the treatment of cognition dysfunction.

In Vivo Profile of ICA-27243 [N-(6-Chloro-pyridin-3-yl)-3,4-difluoro-benzamide], a Potent and Selective KCNQ2/Q3 (Kv7.2/Kv7.3) Activator in Rodent Anticonvulsant Models

“…The effects of KCNQ channels on neuronal excitability make KCNQ blockers potential targets for cognition enhancers, and a number of the earliest KCNQ blockers were developed as cognition-enhancing drugs (Gribkoff, 2003). The KCNQ blocker linopirdine has been shown to enhance cognition in a variety of animal models (Cook et al, 1990;Fontana et al, 1994), although the compound produced equivocal results in human clinical trials (Rockwood et al, 1997;Börjes-son et al, 1999). XE911, a potent blocker of KCNQ channels has also shown in vivo activity suggestive of cognition-enhancing ability (Zaczek et al, 1998).…”

Controlling potassium channel activities: Interplay between the membrane and intracellular factors

“…Moreover, potassium channel blockers and openers have been developed for the purpose of combating convulsion, arrhythmia, or diabetes (5,(13)(14)(15)(16)(17)(18). A better understanding of the potassium channel domains that mediate channel modulation by second messengers, as well as the conformational changes that accompany channel opening and closing, may facilitate future development of use-dependent drugs that affect potassium channels according to their recent and imminent activities.…”

Modulation of Kv7 channels and excitability in the brain

“…However, it took nearly two decades to determine the molecular identity [7]. The lapse in time that was required to elucidate Kv7 as the underling subunits of the M-current was largely due to the lack of available tools able to link cloned channels to native M-current [14]. On the heels of this discovery numerous facets involved in the modulation of the Kv7 channel complex have also been uncovered.…”