Copyright © 1998 by Institute of Pharmacology
Polish Academy of Sciences 		Pol. J. Pharmacol., 1998, 50, 333-340
ISSN 1230-6002
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1,4-BENZOXAZIN-3(4H)-ONE DERIVATIVES AND RELATED COMPOUNDS AS 5-HT1A AND 5-HT2A RECEPTOR LIGANDS; THE EFFECT OF THE TERMINAL AMIDE FRAGMENT ON THE 5-HT1A/5-HT2A AFFINITY AND FUNCTIONAL ACTIVITY*
 Maria J. Mokrosza#, Piotr Kowalskib, Teresa Kowalskab, Zbigniew Majkab, Beata Duszyńskaa, Sijka Charakchieva-Minola, Anna Szaroa, Ewa Tatarczyńskac, Aleksandra Kłodzińskac, Ewa Chojnacka-Wójcikc
 a Department of Medicinal Chemistry, b Department of New Drug Research, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Kraków, Poland
b Institute of Organic Chemistry and Technology, University of Technology, Warszawska 24, PL 31-155 Kraków, Poland

1,4-Benzoxazin-3(4H)-one derivatives and related compounds as 5-HT1A and 5-HT2A receptor ligands; the effect of the terminal amide fragment on the 5-HT1A/5-HT2A affinity and functional activity. M.J. MOKROSZ, P. KOWALSKI, T. KOWALSKA, Z. MAJKA, B. DUSZYŃSKA, S. CHARAKCHIEVA-MINOL, A. SZARO, E. TATARCZYŃSKA, A. KŁODZIŃSKA, E. CHOJNACKA-WÓJCIK. Pol. J. Pharmacol., 1998, 50, 333–340.

A number of new 1-phenyl- (a), 1-(3-chlorophenyl)- (b) and 1-(2-methoxyphenyl)- (c) piperazine derivatives containing 1,4-benzoxazin-3(4H)-one (2–4), 2,4-benzoxazin-3-(4H)-one (5), 1,2-benzoxazolin-3-one (6) and 1,3-benzoxazolin-2,4-dione (7) were synthesized. Radioligand binding measurements showed that the majority of compounds had a distinct affinity for 5-HT1A (3a, 6a, 2–5b, 6c; Ki = 7.5–81 nM) and/or 5-HT2A (2b, 5–7a,b; Ki = 18–69 nM) receptors. Structure-Activity Relationship (SAR) studies revealed structural features which seem to favour the binding to either or both of these two receptor subtypes. For evaluation of the functional in vivo profile of the most potent 5-HT1A (5b, 6b) and/or 5-HT2A (5–7b) ligands, the following tests were used: the 8-OH-DPAT-induced lower lip retraction (LLR) and behavioral syndrome in rats – for 5-HT1A receptor antagonistic activity, and the (±)DOI-induced head twitches in mice and the (±)DOI-induced discriminative stimulus properties in rats – for 5-HT2A receptor antagonistic properties.
The obtained results show that compounds 5b and 6c behave like potent 5-HT1A antagonists, whereas 5b, 6b and 7b demonstrate 5-HT2A receptor antagonistic properties. None of the in vivo tested compounds, given alone, mimicked 8-OH-DPAT activity in those tests. It seems that derivative 5b, which has an equipotent 5-HT1Aand 5-HT2A affinity and antagonistic properties at both these receptors, is a promising potential psychotropic substance.

Key words: 1,4-benzoxazin-3(4H)-one derivatives, 5-HT1A and 5-HT2A ligands, 5-HT1A and 5-HT2A antagonistic properties
  * Part 36 of the series: Structure-Activity Relationship Studies of CNS Agents
  # correspondence
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