Structure-activity relationship studies of CNS agents. Part 38 - Novel 1,4-benzoxazin-3(4H)-one, 1,2-benzoxazolin-3-one and 1,3-benzoxazolin-2,4-dione arylpiperazine derivatives with different 5-HT1A and antagonistic 5-HT2A activities

New 1-arylpiperazine (series d-f) and 1,2,3,4-tetrahydroisoquinoline (serie s g) derivatives of 1,4-benzoxazin-3(4H)-one 1, 1,2-benzoxazolin-3-one 2, a nd 1,3-benzoxazolin-2,4-dione 3 with an n-butyl chain were synthesized in o rder to explore the effect of spacer elongation on their binding affinity a nd in vivo functional activity at 5-HT1A and 5-HT2A receptors in comparison with trimethylene analogues (a, b c). 5-HT1A receptor binding constants of derivatives 1d-g, 2d-f, and 3d-f were very high (K-i = 1.25-54 nhl), and 5 -HT2A affinities were maintained at a similar, high level (K-i = 27-85 nM) for series d and e, and moderate (K-i = 246-495 nM) for series f. In respec t of a spacer, the obtained results showed either no effect or a slight inc rease in the 5-HT1A/5-HT2A affinity in case of derivatives of 1 and 2, resp ectively. A striking effect was observed for derivatives 3d and 3f, whose 5 -HT1A affinity was reinforced by two orders of magnitude with a simultaneou s decrease in 5-HT2A binding constants in comparison with trimethylene anal ogues. As shown by X-ray crystallography, this phenomenon may be attributed to the position of non-carbonyl oxygen atom in the amide moiety. In vivo s tudies demonstrated that compounds 1e-g, 2d-f, and 3f behaved like typical postsynaptic 5-HT2A receptor antagonists, whereas 3d and 3e might be qualif ied as their potential partial agonists. Moreover, 1e, 2e, and 3e demonstra ted 5-HT2A receptor antagonistic properties. Of the tested compounds, two d erivatives showed some very outstanding properties: 3e may be regarded as a potential anxiolytic and/or antidepressant agent, while 3f as a new potent 5-HT1A antagonist.