ABSTRACT
In the title compound, C25H27NO4S, which crystallized as a racemate, the relative configuration of the adjacent OH and CH3 groups on the azepine ring is trans. The seven-membered azepin ring has a chair-like conformation. The planar aromatic rings of the benzyl and tosyl-ate moiety are inclined to the planar 3-benzazepine ring by 78.39â (15) and 77.03â (14)°, respectively, and to each another by 13.82â (15)°. In the crystal, mol-ecules are linked via O-Hâ¯O and C-Hâ¯O hydrogen bonds, forming double-stranded chains along the a-axis direction. The chains are linked via C-Hâ¯π inter-actions, forming a three-dimensional architecture.
ABSTRACT
The title compounds, C22H29NO2 (3) and C22H29NO2 (4) [systematic names: (1S*,2R*)-7-meth-oxy-2-methyl-3-(4-phenyl-but-yl)-2,3,4,5-tetra-hydro-1H-3-benzazepin-1-ol and (1R*,2R*)-7-meth-oxy-2-methyl-3-(4-phenyl-but-yl)-2,3,4,5-tetra-hydro-1H-3-benzazepin-1-ol, are diastereomers with the relative configuration of the adjacent hydroxyl and methyl groups at the seven-membered azepine ring being trans in (3) and cis in (4). In the crystals the orientation of these groups is -anti-periplanar (3) and +syn-clinal (4). In both cases, the crystals studied proved to be of a racemic mixture, with relative configurations (R*,S*)-3 and (R*,R*)-4. In both compounds, the seven-membered azepine ring has a chair-like conformation, and the 4-phenyl-butyl side chain adopts a extended conformation in (R*,S*)-3, but a twisted conformation in (R*,R*)-4. In the crystal of (S*,R*)-3, mol-ecules are linked via C-Hâ¯O hydrogen bonds, forming slabs parallel to the ac plane. In the crystal of (R*,R*)-4, mol-ecules are linked via O-Hâ¯N hydrogen bonds, forming chains propagating along the c-axis direction. The chains are linked by C-Hâ¯O hydrogen bonds, forming slabs parallel to the ac plane.
ABSTRACT
A chiral pool synthesis was developed to obtain all four stereoisomeric 2-methyl-3-(4-phenylbutyl)tetrahydro-3-benzazepin-1-ols 21, 31, and 32 in a seven- to eight-step sequence. The phenols 32 reveal slightly higher GluN2B affinity than the methyl ethers 21. The GluN2B affinity increases in the order (1R,2S) < (1S,2S) < (1S,2R) < (1R,2R). The stereoisomeric phenols (R,R)-32 and (S,R)-32 show the highest GluN2B affinity and the highest cytoprotective activity. Both compounds represent GluN2B selective allosteric NMDA receptor antagonists. Docking of the 3-benzazepin-1-ols into the ifenprodil binding site of the crystallized GluN1b/GluN2B N-terminal domains led to free binding energies, which correlate nicely with the experimentally determined GluN2B affinities. The similar GluN2B affinity of the stereoisomeric phenols (S,S)-32, (R,R)-32, and (S,R)-32 is explained by different binding modes of the 3-benzazepine scaffold. The benzyl ethers 31 reveal unexpectedly high GluN2B affinity but do not show cytoprotective effects. The additional benzyl moiety of 31 binds into a previously unrecognized lipophilic subpocket.
Subject(s)
Benzazepines/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Benzazepines/chemistry , Excitatory Amino Acid Antagonists/chemistry , Molecular Docking Simulation , Stereoisomerism , Structure-Activity RelationshipABSTRACT
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-1H-3-benzazepine-1,7-diol (WMS-1410, 25) represents the most promising NR2B antagonist of this series showing a K(i)-value of 14nM. Compound 25 reveals excellent selectivity over more than 100 further relevant target proteins, antagonizes glutamate induced excitotoxicity (IC(50)=18.4nM) and is metabolically more stable than ifenprodil. Up to a dose of 100mg/kg 25 is well tolerated by mice and it shows dose dependent analgesic activity in the late neuropathic pain phase of the formalin assay.
Subject(s)
Analgesics/chemical synthesis , Benzazepines/chemistry , Piperidines/chemistry , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Analgesics/chemistry , Analgesics/therapeutic use , Animals , Benzazepines/chemical synthesis , Benzazepines/therapeutic use , Humans , Mice , Microsomes, Liver/metabolism , Neuralgia/drug therapy , Rats , Receptors, N-Methyl-D-Aspartate/metabolism , Structure-Activity RelationshipABSTRACT
A selective, rapid and efficient competitive binding assay for the determination of the affinity of compounds towards the ifenprodil binding site of NR2B subunit containing NMDA receptors has been developed. In the assay system, [(3)H]ifenprodil was used as radioligand and membrane homogenates from L(tk-) cells stably expressing recombinant human NR1a/NR2B receptors served as the receptor material. Sonication of the cells during work-up, performing all steps with 96-well multiplates and using a solid scintillator represent particular features of this assay. The binding kinetics was investigated by saturation and association/dissociation experiments. [(3)H]ifenprodil bound to a single, saturable site on human recombinant NR1a/NR2B receptors, resulting in a B(max)-value of 25.8 pmol/microg protein and K(d)-value of 7.6+/-2.3 nM (SEM). The dissociation rate constant (k(off)) was 0.03861 min(-1) and the association rate constant k(on) resulted in 0.00625 nM(-1)min(-1). The specificity of the assay was proved with cells not treated with dexamethasone, which has to be added to induce NMDA receptor synthesis of the cells. Additionally, the absence of alpha(1), sigma(1) and sigma(2) receptors was shown. The K(i)-values of the NR2B ligands ifenprodil and eliprodil determined with the new assay are in good accordance with reported data.
Subject(s)
Piperidines/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Animals , Binding, Competitive , Cells, Cultured , Humans , Mice , Radioligand AssayABSTRACT
Cleavage and reconstitution of a bond in the piperidine ring of ifenprodil (1) leads to 7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-1-ols, a novel class of NR2B-selective NMDA receptor antagonists. The secondary amine 7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-1-ol (12), which was synthesized in six steps starting from 2-phenylethylamine 3, represents the central building block for the introduction of several N-linked residues. A distance of four methylene units between the basic nitrogen atom and the phenyl residue in the side chain results in high NR2B affinity. The 4-phenylbutyl derivative 13 (WMS-1405, K(i)=5.4 nM) and the conformationally restricted 4-phenylcyclohexyl derivative 31 (K(i)=10 nM) represent the most potent NR2B ligands of this series. Whereas 13 shows excellent selectivity, the 4-phenylcyclohexyl derivative 31 also interacts with sigma(1) (K(i)=33 nM) and sigma(2) receptors (K(i)=82 nM). In the excitotoxicity assay the phenylbutyl derivative 13 inhibits the glutamate-induced cytotoxicity with an IC(50) value of 360 nM, indicating that 13 is an NMDA antagonist.