Synthesis and structure/NMDA receptor affinity relationships of 1-substituted tetrahydro-3-benzazepines.
A novel synthesis of 1-substituted tetrahydro-1H-3-benzazepines 4 is described. Starting with (2-bromophenyl)acetaldehyde acetal 5, the nitrostyrene 9 was prepared in three steps allowing the addition of various nucleophiles to yield the nitroacetals 10. The one-pot Zn/HCl reductive cyclization of the nitroacetals 10 provided the 3-benzazepines 4, which were investigated for their affinity to the phencyclidine binding site of the NMDA receptor. A one-atomic spacer between the 3-benzazepine system and the phenyl residue in position 1 seems to be favorable for high NMDA receptor binding. In this series the benzazepine 4l substituted with the conformationally restricted and H-bond accepting acetanilide substituent in position 1 displays the highest NMDA receptor affinity (K(i)=89 nM).
Krull
Olaf
O
Institut für Pharmazeutische und Medizinische Chemie der, Westfälischen Wilhelms-Universität Münster, Hittorfstrasse 58-62, D-48149 Münster, Germany.
Wünsch
Bernhard
B
D000818:Animals; D001552:Benzazepines / Q000138:chemical synthesis* / Q000378:metabolism* / Q000494:pharmacology; D001665:Binding Sites; D002462:Cell Membrane / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006860:Hydrogen Bonding; D008968:Molecular Conformation; D015394:Molecular Structure; D010622:Phencyclidine / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013552:Swine
D001552:Benzazepines; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D010622:Phencyclidine