Influence of the aliphatic spacer length on the 5-HT1A receptor activity of new arylpiperazines with an indazole system.
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 three-methylene analogs (1b and 2b) described earlier. Both dimethylene derivatives (la 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).
Paluchowska
M H
MH
Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, Kraków.
Duszyńska
B
B
Kłodzińska
A
A
Tatarczyńska
E
E
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D008046:Lip / Q000187:drug effects; D008297:Male; D005082:Physical Exertion / Q000187:drug effects; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects*; D044263:Receptors, Serotonin, 5-HT1; D012110:Reserpine / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013329:Structure-Activity Relationship
D014150:Antipsychotic Agents; D010879:Piperazines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D012110:Reserpine