Graham Johnson and Paul L. Ornstein Pages 331 - 356 ( 26 )
The N-methyl-D-aspartic acid (NMDA) receptor subclass of excitatory amino acid receptors is among the most extensively studied of this class of receptors. Ample evidence supports the potential therapeutic application of NMDA antagonists in the treatment of acute and chronic neurotrauma, and as anticonvulsant and analgesic agents. This review summarizes some of the current knowledge regarding the molecular biology of NMDA receptors. At least two distinct classes of proteins have been identified which comprise NMDA receptors in the CNS, and the relative distribution of these two proteins throughout the CNS may account for NMDA receptor homogeneity. This review also discusses structure activity relationships of competitive NMDA antagonists, i.e., compounds which compete with the endogenous excitatory amino acid glutamate at its recognition site. Structural modifications of the prototypical competitive NMDA antagonist 2- amino-5-phosphonopentanoic acid (AP5) which impart greater potency are discussed. These include incorporation of the AP5 substructure into cyclic systems or incorporation of functionality onto the backbone of AP5 to constrain conformational mobility; biososteric replacement of the distal phosphonic acid; and biososteric replacement of the proximal α-amino acid.). Stereochemical requirements for binding of these novel antagonist ligands are also discussed, along with three attempts to understand ligand-protein interactions at this receptor using molecular modeling techniques.