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Copyright © 2000 by Institute of Pharmacology Polish Academy of Sciences |
Pol. J. Pharmacol., 2000, 52, 209-216 ISSN 1230-6002 |
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Influence of the aliphatic spacer length on the 5-HT1A receptor activity of new arylpiperazines with an indazole system.
M.H. PALUCHOWSKA, B. DUSZYŃSKA, A. KŁODZIŃSKA, E. TATARCZYŃSKA. Pol. J. Pharmacol., 2000, 52, 209-216. Novel arylpiperazines (1a, 1c, 2a and 2c), containing a terminal 1- or 2-indazolyl fragment and a di- or tetramethylene aliphatic spacer, were synthesized and their 5-HT1A and 5-HT2A receptor affinities were determined. All those compounds showed a potent affinity for 5-HT1A receptors (Ki = 5–16 nM) and were evaluated for an intrinsic activity at those receptors. In order to determine a 5-HT1A agonistic effect of the investigated compounds, their ability to induce a lower lip retraction in rats and a behavioral syndrome (flat body posture and forepaw treading) in reserpinized rats were tested, whereas their 5-HT1A antagonistic activity was assessed via inhibition of those symptoms produced by 8-hydroxy-2-di-n-propylamino)tetralin hydrobromide (8-OH-DPAT). The effect of spacer length on the 5-HT1A activity of the tested compounds was discussed in comparison with that of the threemethylene analogs (1b and 2b) described earlier. Both dimethylene derivatives (1a and 2a) were characterized as weak postsynaptic 5-HT1A receptor antagonists. Compounds 1c (1-indazolyl analog) and 2c (2-indazolyl analog) with a tetramethylene aliphatic chain were classified as a postsynaptic 5-HT1A antagonist and a partial 5-HT1A agonist, respectively. Furthermore, the latter showed a moderate anxiolytic-like effect (conflict drinking Vogel’s test in rats) and a weak antidepressant-like activity (forced swimming Porsolt’s test in rats). Key words: arylpiperazine 5-HT1A ligands, structure-activity relationship, anxiolytic- and antidepressant-like activities, rat |
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