Novel N-methyl-D-aspartate receptor antagonists: a review of compounds patented since 2006.
BACKGROUND
The NMDA receptor is a complex ligand gated, voltage-dependent ion channel. It has been a drug target for > 25 years for neurological and psychiatric indications. Whereas the initial optimism to turn preclinically active compounds rapidly into drugs for human use was dampened, new insights into cellular receptor localization, role of subunits and receptor operation have kept the interest alive to modulate this receptor for therapeutic intervention.


METHODS
The article describes the NMDA receptor antagonists patented since 2006. Also included are novel NMDA receptor ligands potentially useful for positron emission tomography imaging.


RESULTS
The first section summarizes the current status of NMDA receptor pharmacology. This serves as a base for the next sections discussing the patented compounds with respect to their mode of action, potency and, in some cases, drugability.


CONCLUSIONS
The most important recent strategies aiming for inhibition of NMDA receptor-mediated neurotransmission avoid for safety reasons full receptor blockade but allow a low degree of normal receptor function. Approaches pursued by the latest patents comprise blocking the channel with compounds of low affinity, antagonizing receptor activity by highly potent NR2B ligands, partial agonism at the glutamate or glycine-binding site and improvement of pharmacokinetic properties of well established, safe antagonists by deuteration.
Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Basel, Switzerland. manuel.koller@novartis.com
Manuel
M
Koller
Stephan
S
Urwyler
D000818:Animals; D016503:Drug Delivery Systems; D015195:Drug Design; D006801:Humans; D008024:Ligands; D010330:Patents as Topic; D049268:Positron-Emission Tomography / Q000379:methods*; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism
D008024:Ligands; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate