Synthesis and pharmacological characterization of novel 6-fluorochroman derivatives as potential 5-HT(1A) receptor antagonists

Article abstract of DOI:10.1021/jm9707840

A series of novel 6-fluorochroman derivatives was prepared and evaluated as antagonists for the 5-HT(1A) receptor. N-2-[[(6-Fluorochroman-8- yl)oxy]ethyl]-4-(4-methoxyphenyl)butylamine (3; J. Med. Chem. 1997, 40, 1252- 1257) was chosen as a lead, and structural modifications were done on the aliphatic portion of the chroman ring, the tether linking the middle amine and the terminal aromatic ring, the aromatic ring, and lastly the amine. Radioligand binding assays proved that the majority of the novel compounds behaved as good to excellent ligands at the 5-HT(1A) receptor, some of which were selective with respect to α₁-adrenergic and D₂-dopaminergic receptors. The antagonist activity of the compounds was assessed in the forskolinstimulated adenylate cyclase assays in CHO cells expressing the human 5-HT(1A) receptors. Among the modifications attempted, introduction of an oxo or an optically active hydroxy moiety at the chroman C-4 position was effective in ameliorating the receptor selectivity. Six analogues were selected through the in vitro screens and further evaluated for their in vivo activities. A 4-oxochroman derivative (31n), having a terminal 1,3- benzodioxole ring, demonstrated antagonist activities toward 8-OH-DPAT- induced behavioral and electrophysiological responses in rats.