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Novel 1,4‐Benzoxazin‐3( 4H )‐one, 1,2‐Benzoxazolin‐3‐one and 1,3‐Benzoxazolin‐2,4‐dione Arylpiperazine Derivatives with Different 5‐HT 1A and Antagonistic 5‐HT 2A Activities
Author(s) -
Mokrosz Maria J.,
Kowalski Piotr,
Kowalska Teresa,
Majka Zbigniew,
Duszynska Beata,
Bojarski Andrzej J.,
Fruzinski Andrzej,
KarolakWojciechowska Janina,
Wesolowska Anna,
Klodzinska Aleksandra,
Tatarczynska Ewa,
ChojnackaWojcik Ewa
Publication year - 1999
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/(sici)1521-4184(199911)332:11<373::aid-ardp373>3.0.co;2-l
Subject(s) - chemistry , stereochemistry , moiety , amide , 5 ht1a receptor , affinities , in vivo , receptor , 5 ht receptor , serotonin , organic chemistry , biochemistry , microbiology and biotechnology , biology
New 1‐arylpiperazine (series d—f ) and 1,2,3,4‐tetrahydroisoquinoline (series g ) derivatives of 1,4‐benzoxazin‐3( 4H )‐one 1, 1,2‐benzoxazolin‐ 3‐one 2 , and 1,3‐benzoxazolin‐2,4‐dione 3 with an n ‐butyl chain were synthesized in order to explore the effect of spacer elongation on their binding affinity and in vivo functional activity at 5‐HT 1A and 5‐HT 2A receptors in comparison with trimethylene analogues ( a, b c ). 5‐HT 1A receptor binding constants of derivatives 1d—g , 2d—f , and 3d—f were very high ( K i = 1.25—54 nM), and 5‐HT 2A 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 respect of a spacer, the obtained results showed either no effect or a slight increase in the 5‐HT 1A /5‐HT 2A affinity in case of derivatives of 1 and 2 , respectively. A striking effect was observed for derivatives 3d and 3f , whose 5‐HT 1A affinity was reinforced by two orders of magnitude with a simultaneous decrease in 5‐HT 2A binding constants in comparison with trimethylene analogues. 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 studies demonstrated that compounds 1e—g , 2d—f , and 3f behaved like typical postsynaptic 5‐HT 1A receptor antagonists, whereas 3d and 3e might be qualified as their potential partial agonists. Moreover, 1e , 2e , and 3e demonstrated 5‐HT 2A receptor antagonistic properties. Of the tested compounds, two derivatives showed some very outstanding properties: 3e may be regarded as a potential anxiolytic and/or antidepressant agent, while 3f as a new potent 5‐HT 1A antagonist.