Pharmacological modulation of NMDA receptor activity and the advent of negative and positive allosteric modulators |
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Authors: | Monaghan Daniel T Irvine Mark W Costa Blaise Mathias Fang Guangyu Jane David E |
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Affiliation: | Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA. |
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Abstract: | The NMDA receptor (NMDAR) family of l-glutamate receptors are well known to have diverse roles in CNS function as well as in various neuropathological and psychiatric conditions. Until recently, the types of agents available to pharmacologically regulate NMDAR function have been quite limited in terms of mechanism of action and subtype selectivity. This has changed significantly in the past two years. The purpose of this review is to summarize the many drug classes now available for modulating NMDAR activity. Previously, this included competitive antagonists at the l-glutamate and glycine binding sites, high and low affinity channel blockers, and GluN2B-selective N-terminal domain binding site antagonists. More recently, we and others have identified new classes of NMDAR agents that are either positive or negative allosteric modulators (PAMs and NAMs, respectively). These compounds include the pan potentiator UBP646, the GluN2A-selective potentiator/GluN2C and GluN2D inhibitor UBP512, the GluN2D-selective potentiator UBP551, the GluN2C/GluN2D-selective potentiator CIQ as well as the new NMDAR-NAMs such as the pan-inhibitor UBP618, the GluN2C/GluN2D-selective inhibitor QZN46 and the GluN2A inhibitors UBP608 and TCN201. These new agents do not bind within the l-glutamate or glycine binding sites, the ion channel pore or the N-terminal regulatory domain. Collectively, these new allosteric modulators appear to be acting at multiple novel sites on the NMDAR complex. Importantly, these agents display improved subtype-selectivity and as NMDAR PAMs and NAMs, they represent a new generation of potential NMDAR therapeutics. |
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Keywords: | ATP, adenosine-5’-triphosphate AMPA, (S)-2-amino-3-hydroxy-5-methylisoxazole-4-propionic acid D-α–AA, D-α-amino adipate D-AP5, (D-2-amino-5-phosphonopentanoic acid) CIQ, (3-chlorophenyl)(6,7-dimethoxy-1-((4-methoxyphenoxy)methyl)-3,4-dihydroisoquinolin-2(1H)-ylmethanone CP-101, 606, (1S,2S)-1-(4-hydroxy-phenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol CPP, (RS)-4-(3-phosphonopropyl)piperazine-2-carboxylic acid DQP-1105, 4-(5-(4-bromophenyl)-3-(6-methyl-2-oxo-4-phenyl-1,2-dihydroquinolin-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid GluN, NMDA family of glutamate receptor subunits GYKI52466, 4-(8-methyl-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepin-5-yl)benzeneamine dihydrochloride HA-966, (RS)-3-amino-1-hydroxypyrrolidin-2-one L-683,344, 7-chloro-4-hydroxy-5-iodoquinoline-2-carboxylic acid L-701,324, 7-chloro-4-hydroxy-3-(3-phenoxy)phenyl-2(1H)-quinolinone LBD, ligand binding domain LTD, long term depression LTP, long term potentiation M, membrane-associated domain MDL-105,519, (E)-4,6-dichloro-3-(2-phenyl-2-carboxyethenyl)indole-2-carboxylic acid MK-801, (5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine NAM, negative allosteric modulator neu2000, 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)benzoic acid NMDA, N-methyl-D-aspartate NTD, amino terminal domain NVP-AAM077, ([(R)-[(S)-1-(4-bromophenyl)ethylamino]-(2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl)methyl]-phosphonic acid, (1RS,1′S)-PEAQX ([(RS)-[(S)-1-(4-bromophenyl)ethylamino]-(2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl)methyl]-phosphonic acid PAM, positive allosteric modulator PPDA, ((2R∗,3S∗)-1-(phenanthrene-2-carbonyl)piperazine-2,3-dicarboxylic acid) PS, pregnenolone sulfate QNZ46, (E)-4-(6-methoxy-2-(3-nitrostyryl)-4-oxoquinazolin-3(4H)-yl)-benzoic acid S, segment Ro25-6981, (αR,βS)-α-(4-hydroxyphenyl)-β-methyl-4-(phenylmethyl)-1-piperidinepropanol TCN 201, (3-chloro-4-fluoro-N-[(4-{[2-(phenylcarbonyl)hydrazino]carbonyl} phenyl)methyl]benzene-sulfonamide) TMD, transmembrane domain TPA, tissue plasminogen activator UBP141, ((2R∗,3S∗)-1-(phenanthrene-3-carbonyl)piperazine-2,3-dicarboxylic acid) UBP145, ((2R∗,3S∗)-1-(9-bromophenanthrene-3-carbonyl)piperazine-2,3-dicarboxylic acid) UBP161, (2R∗,3S∗)-1-(9-iodophenanthrene-3-carbonyl)piperazine-2,3-dicarboxylic acid UBP512, 9-iodophenanthrene-3-carboxylic acid UBP551, 3,5-dihydroxynaphthalene-2-carboxylic acid UBP608, 6-bromocoumarin-3-carboxylic acid UBP618, 1-bromo-2-hydroxy-6-phenylnaphthalene-3-carboxylic acid UBP646, 9-(4-methylpent-1-yl) phenanthrene-3-carboxylic acid UBP710, 9-cyclopropylphenanthrene-3-carboxylic acid |
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