SYNTHESIS AND PHARMACOLOGICAL CHARACTERIZATION OF NOVEL 6-FLUOROCHROMAN DERIVATIVES AS POTENTIAL 5-HT1A RECEPTOR ANTAGONISTS

A series of novel 6-fluorochroman derivatives was prepared and evaluat ed as antagonists for the 5-HT1A receptor. N-2- oman-8-yl)oxy]ethyl]-4 -(4-methoxyphenyl)butylamine (3; J. Med. Chem. 1997, 40, 1252-1257) wa s chosen as a lead, and structural modifications were done on the alip hatic portion of the chroman ring, the tether linking the middle amine and the terminal aromatic ring, the aromatic ring, and lastly the ami ne. Radioligand binding assays proved that the majority of the novel c ompounds behaved as good to excellent ligands at the 5-HT1A receptor, some of which were selective with respect to alpha(1)-adrenergic and D -2-dopaminergic receptors. The antagonist activity of the compounds wa s assessed in the forskolin-stimulated adenylate cyclase assays in CHO cells expressing the human 5-HT1A receptors. Among the modifications attempted, introduction of an oxo or an optically active hydroxy moiet y at the chroman C-4 position was effective in ameliorating the recept or selectivity. Six analogues were selected through the in vitro scree ds and further evaluated for their in vivo activities. A 4-oxochroman derivative (31n), having a terminal 1,3-benzodioxole ring, demonstrate d antagonist activities toward 8-OH-DPAT-induced behavioral and electr ophysiological responses in rats.