Cognition Enhancing Profile of CR 2249, a New NMDA‐Glycine Site Modulator

Abstract

Memory processes have been widely studied in recent decades. Unfortunately, although several intriguing hypotheses about the possibility of modulating cognition have been developed, no conclusive result has been obtained (69). Two different neurotransmission models are of major interest in understanding how the brain can acquire and store a single cognitive event (3,23). The main neuronal agents involved in transferring this kind of information seem to be acetylcholine and glutamic acid. These two neurotransmitters are present in all the cerebral areas involved in the memory processes and both are responsible for the stimulation currents linked to the propagation of neuronal signals (1,4). The cholinergic hypothesis of memory ( 3 ) is based on the observation that a marked degeneration of the cholinergic neuronal pathway is often associated with the development of cognitive disorders ( 12). Moreover, it has been reported that one distinctive feature of Alzheimer’s disease (AD) consists of a progressive loss of either cholinergic or adrenergic neurons’ ability to transmit stimuli received from the limbic areas to the cerebral cortex (10,12,21,75). To help preserve high levels of acetylcholine in the synaptic cleft, several antiacetylcholinesterase agents have been synthesized and tested on both biochemical and behavioral models of learning (32,46). Tacrine is certainly the most studied among these agents ( 13). Clinical trials with tacrine revealed some interesting pro-mnemic properties of this compound (42,68), but tacrine exhibits major hepatotoxicity that strongly restricts its use ( 13,73). Donepezil (E2020) is another interesting compound of this family. Two recently published clinical studies (25,63) demonstrate both the efficacy of donepezil in patients with mild-to-moderate Alzheimer’s disease and its relative liver safety. Other potent acetylcholinesterase inhibitors, such as metrifonate and SDZ ENA 7 13, are currently under clinical evaluation (28,62,65). The glutamatergic hypothesis of memory is based on a particular characteristic of the glutamatergic neuronal pathway: long-term potentiation (LTP). LTP was first defined by Bliss and Collingridge (8) as a synaptic memory model expressed as a persistent increase in the size of the synaptic component of the evoked response. The