Conformationally constrained NR2B selective NMDA receptor antagonists derived from ifenprodil: Synthesis and biological evaluation of tetrahydro-3-benzazepine-1,7-diols

• Published in: Bioorganic & medicinal chemistry Vol. 18; no. 22; pp. 8005 - 8015
• Main Authors: Tewes, Bastian, Frehland, Bastian, Schepmann, Dirk, Schmidtke, Kai-Uwe, Winckler, Thomas, Wünsch, Bernhard
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15-11-2010; Elsevier
• Subjects: 3-Benzazepines; Amino groups; Analgesics; Analgesics - chemical synthesis; Analgesics - chemistry; Analgesics - therapeutic use; Animals; Benzazepines - chemical synthesis; Benzazepines - chemistry; Benzazepines - therapeutic use; Biological and medical sciences; Glutamatergic system (aspartate and other excitatory aminoacids); Humans; Medical sciences; Mice; Microsomes, Liver - metabolism; Neuralgia - drug therapy; Neuropathic pain; Neuropharmacology; Neuroprotection; Neuroprotective agent; Neurotransmitters. Neurotransmission. Receptors; NR2B selective NMDA receptor antagonists; Pharmacology. Drug treatments; Piperidines - chemistry; Rats; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - metabolism; Structure-Activity Relationship; Structure–activity relationships; Neuroprotection; 3-Benzazepines; Structure–activity relationships; NR2B selective NMDA receptor antagonists; Neuropathic pain; Intraperitoneal administration; Nitrogen heterocycle; Glutamate receptor; Selectivity; Structure-activity relationships; Structure activity relation; Bicyclic compound; Antagonist; Chemical synthesis; Molecular rigidity; Aminoalcohol; Rodentia; Steric hindrance; Neuroprotective agent; In vitro; In vivo; Vertebrata; Mammalia; Analgesic; Mouse; Animal; Phenols; Affinity; NMDA receptor
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2010.09.026

NR2B selective NMDA receptor antagonists with tetrahydro-3-benzazepine-1,7-diol scaffold have been designed by formal cleavage and reconstitution of the piperidine ring of the lead compound ifenprodil (
1). The secondary amine
10 represents the central building block for the synthesis of more than 25 tetrahydro-3-benzazepin-1-ols. Generally 7-hydroxy derivatives display higher NR2B receptor affinities than the corresponding 7-benzyloxy compounds. A distance of four atoms (five bond lengths) between the basic amino group and the terminal aryl moiety led to highest NR2B affinity. 3-(4-Phenylbutyl)-2,3,4,5-tetrahydro-1
H-3-benzazepine-1,7-diol (WMS-1410,
25) represents the most promising NR2B antagonist of this series showing a
K
i-value of 14
nM. Compound
25 reveals excellent selectivity over more than 100 further relevant target proteins, antagonizes glutamate induced excitotoxicity (IC
50
=
18.4
nM) and is metabolically more stable than ifenprodil. Up to a dose of 100
mg/kg
25 is well tolerated by mice and it shows dose dependent analgesic activity in the late neuropathic pain phase of the formalin assay.