Role of the phenolic OH moiety of GluN2B-selective NMDA antagonists with 3-benzazepine scaffold (original) (raw)
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Bioorganic & Medicinal Chemistry, 2018
The NMDA receptor containing GluN2B subunits represents a promising target for the development of drugs for the treatment of various neurological disorders including neurodegenerative diseases. In order to study the role of CH 3 and OH moieties trisubstituted tetrahydro-3-benzazepines 4 were designed as missing link between tetra-and disubstituted 3-benzazepines 2 and 5. The synthesis of 4 comprises eight reaction steps starting from alanine. The intramolecular Friedel-Crafts acylation to obtain the ketone 12 and the base-catalyzed elimination of trifluoromethanesulfinate (CF 3 SO 2 À) followed by NaBH 4 reduction represent the key steps. The GluN2B affinity of the cis-configured 3-benzazepin-1-ol cis-4a with a 4phenylbutyl side chain (K i = 252 nM) is considerably lower than the GluN2B affinity of (R,R)-2 (K i = 17 nM) indicating the importance of the phenolic OH moiety for the interaction with the receptor protein. Introduction of an additional CH 3 moiety in 2-position led to a slight decrease of GluN2B affinity as can be seen by comparing the affinity data of cis-4a and 5. The homologous phenylpentyl derivative cis-4b shows the highest GluN2B affinity (K i = 56 nM) of this series of compounds. According to docking studies cis-4a adopts the same binding mode as the cocrystallized ligand ifenprodil-keto 1A and 5 at the interface of the GluN2B and GluN1a subunits. The same crucial H-bonds are formed between the C(@O) NH 2 moiety of Gln110 within the GluN2B subunit and the protonated amino moiety and the OH moiety of (R,R)-cis-4a.
Benzimidazolone bioisosteres of potent GluN2B selective NMDA receptor antagonists
Overactivation of the NMDA receptor is associated with excitotoxic events leading to neurodegenerative processes as observed during the development of Alzheimer's disease, ParFnson's disease, Chorea Huntington and epilepsy. Negative allosteric modulators addressing selectively the ifenprodil binding site of GluN2B subunit containing NMDA receptors are of major interest due to their neuroprotective potential accompanied by few side effects. Herein benzimidazolone bioisosteres of potent GluN2B antagonists 1e5 were designed and synthesized. A seven step sequence provided the central intermediate 19 in 28% yield. Elimination of water, methylation, epoxidation, epoxide rearrangement and finally reductive amination afforded the [7]annulenobenzimidazolone 30 with a 3-phenylpropylamino substituent in 6-position. Although 30 fits nicely into the pharmacophore of potent GluN2B antagonists, the gluN2B binding affinity of 30 was only moderate (K i ¼ 697 nM). Additionally, 30 shows low selectivity over the s 2 receptor (K i ¼ 549 nM). The moderate GluN2B affinity was explained by the rigid tricyclic structure of the [7]annulenobenzimidazolone 30.
Chemical Biology & Drug Design, 2012
The N-methyl-D-aspartic acid (NMDA) receptors are a group of ionotropic glutamate receptors that plays an important role in different physiological functions, including the neuronal development, synaptic plasticity, learning, and memory (1). NMDA receptor is composed of multiple protein subunits, GLUN1, GLUN2 (A-D), and GLUN3 (A-B) in different combinations. In general, the physiological receptor is a heteromer, containing GLUN1 subunit with one or two GLUN2 subunits, but different compositions may occur (2-4). Therefore, depending on the receptor composition both the electrophysiological and pharmacological properties may vary (4). Due to its role, the over-stimulation of NMDA receptor has been implicated in several pathological conditions, involving neuronal death and degeneration (e.g., thrombo-embolic stroke, traumatic head injury, Parkinson's, Huntington's, and Alzheimer's diseases). Therefore, this pathological role has driven the search for NMDA receptor antagonists as a promising therapy (5-8). Currently, the use of NMDA receptor antagonists for acute and chronic neuronal diseases
Earlier, the methoxycarbonylmethyl fragment at the 1 position and the nitrophenylamine frag ment at the 3 position of the 1,4 benzodiazepine ring, on the base of the QSAR analysis of series of 1,4 benzodi azepin 2 one derivatives [1], have been shown to gave compounds with increased affinity for peripheral benzo diazepine receptors (PBR). The 3 arylamine derivatives of 1 methoxycarbonylmethyl 7 bromo 5 phenyl 1,2 dihydro 3H 1,4 benzodiazepin 2 one were proposed for the directed synthesis as a promising high selective li gands of PBR. The target compounds were synthesized through the condensation of 1 methoxycarbonylmethyl 3 chloro 7 bromo 5 phenyl 1,2 dihydro 3H 1,4 benzodiazepin 2 one with substituted anilines. Affinities of synthesized compounds for the CNS benzodiazepine receptors of peripheral (PBR) and central (CBR) types were determined by the radioligand method in vitro. Selective PBR ligand with a high affinity-1 methoxycar bonylmethyl 3 (2' nitro)phenylamino 7 bromo 5 phenyl 1,2 dihydro 3H 1,4 benzodiazepin 2 one, 7 (MX 1785, K i (PBR)=19.1 nM, K i (CBR)>10000 nM) was found among the studied compounds.
A novel binding mode reveals two distinct classes of NMDA receptor GluN2B-selective antagonists
Molecular pharmacology, 2016
NMDA receptors (NMDARs) are glutamate-gated ion channels that play key roles in brain physiology and pathology. Because numerous pathological conditions involve NMDAR overactivation, subunit-selective antagonists hold strong therapeutic potential, although clinical successes remain limited. Among the most promising NMDAR-targeting drugs are allosteric inhibitors of GluN2B-containing receptors. Since the discovery of ifenprodil, a range of GluN2B-selective compounds with strikingly different structural motifs have been identified. This molecular diversity raises the possibility of distinct binding sites, although supporting data are lacking. Using x-ray crystallography, we show that EVT-101, a GluN2B antagonist structurally unrelated to the classical phenylethanolamine pharmacophore, binds at the same GluN1/GluN2B dimer interface as ifenprodil but adopts a remarkably different binding mode involving a distinct subcavity and receptor interactions. Mutagenesis experiments demonstrate t...
Asian Journal of Pharmaceutical and Clinical Research, 2022
Objectives: High Ca 2+ permeability represents a characteristic feature of N-methyl-D-aspartate (NMDA) receptors that in extreme amounts affects physiological functions such as reduced neural development, synaptic plasticity, and learning and memory. The study aims to elucidate the potent inhibitory ifenprodil and their eleven analogues, retrieved from the PubChem database, which act as ligands to the target Glun1/GluN2B subunit of the NMDA receptor. Methods: In silico methods such as molecular docking performed using AutoDock Vina and absorption-distribution-metabolism-excretion-toxicity (ADMET) were SwissADME and OSIRIS carried out to elucidate the potent antagonist ligand against the target. Results: Molecular docking showed that six of the compounds had significant binding affinities (7.8-9.0 kcal/mol) for the target. The ADMET study revealed that three (PubChemID: 12613159, 12613162, and 6604117) of six compounds with good binding affinity obeyed Lipinski's rule of five. Conclusion: This study revealed three good antagonists of GluN1/GluN2B, namely, 4-[(1R, 2R)-2-(4-benzylpiperidin-1-yl)-1-hydroxy propyl] phenol (A2), 4-[2-(4-benzylpiperidin-1-yl)-1-hydrooxypropyl] phenol hydrobromide (A4), and 4-[(1R, 2S)-2-(4-benzylpiperidin-1-yl)-1-hydroxypropyl] phenol (A7) that can be further exploited for wet lab studies.
Bioorganic & Medicinal Chemistry Letters, 2014
GluN2B subtype-selective NMDA antagonists represent promising therapeutic targets for the symptomatic treatment of multiple CNS pathologies. A series of N-benzyl substituted benzamidines were synthesised and the benzyl ring was further replaced with various polycyclic moieties. Compounds were evaluated for activity at GluN2B containing NMDA receptors where analogues 9, 12, 16 and 18 were the most potent of the series, replacement of the benzyl ring with polycycles resulted in a complete loss of activity.