Relating NMDA receptor function to receptor subunit composition: limitations of the pharmacological approach.

Over 20 years of pharmacological, physiological , and genetic studies have established that NMDA receptors (NMDARs), a subtype of ionotropic glutamate receptors , play key roles in numerous physiological and pathological processes in the brain (Dingledine et al., 1999). In particular , activation of NMDARs is required for long-term potentiation (LTP) and long-term depression (LTD), the two major forms of synaptic plasticity that are proposed to underlie learning and memory. NMDARs are heterotetramers composed of NR1 and NR2(A–D) subunits (and more rarely, NR3 subunits), and their functional properties are strongly influenced by the type of NR2 subunit incorporated (Cull-Candy et al., 2001). The four NR2 subunits have distinct distributions in the CNS, with patterns of expression that change drastically during development. Whereas in the embryo, only NR2B and NR2D subunits are expressed, NR2A predominates in the adult brain, being ubiquitously expressed, whereas NR2B expression is restricted to the fore-brain and NR2C is highly enriched in the cerebellum. The existence of distinct NMDAR subpopulations raises the attractive possibility that different receptor subtypes play different roles in the brain, and relating receptor subunit composition to receptor function has become a major challenge in the glutamate receptor field (Cull-Candy and Leszkiewicz, 2004). For this purpose, having subtype-selective antagonists might be of great help. This is best exemplified by ifenprodil and derivatives , a class of compounds that selectively inhibit NR2B-containing receptors and have proven useful in elucidating several roles of this receptor population in brain functions and dysfunctions (Cull-Candy and Leszkiewicz, 2004). Recently, Auber-son et al. reported the discovery of a new NMDAR antagonist [(1 RS,1ЈS)-PEAQX (Auberson et al., 2002) and its active diastereoisomer