Novel 4-alkyl-1-arylpiperazines and 1,2,3,4-tetrahydroisoquinolines containing diphenylmethylamino or diphenylmethoxy fragment with differentiated 5-HT1A/5-HT2A/D2 receptor activity |
| |
Authors: | Paluchowska Maria H Mokrosz Maria J Charakchieva-Minol Sijka Duszyńska Beata Kozio? Aneta Weso?owska Anna Stachowicz Katarzyna Chojnacka-Wójcik Ewa |
| |
Institution: | Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, PL 31-343 Kraków, Poland. |
| |
Abstract: | Two series of 4-alkyl-1-arylpiperazines (1-4) and 1,2,3,4-tetrahydroiso-quinolines (5, 6) with diphenylmethylamino (series a) or diphenylmethoxy (series b) fragment were synthesized in order to obtain potential ligands of 5-HT1A and/or 5-HT2A and dopamine D2 receptors. Four new arylpiperazines (1a, 3a, 1b, 3b) were found to demonstrate high 5-HT1A receptor affinity (Ki = 1.5-35 nM); among them, 3a exhibited satisfactory 5-HT2A receptor affinity (Ki = 74 nM). Only compounds 1b and 2b showed moderate affinity for D2 receptor sites (Ki = 123 and 128 nM, respectively). Compounds 1a, 3a, 1b and 3b were investigated in vivo to determine their functional activity at 5-HT1A receptors; additionally, 3a was tested for 5-HT2A receptor activity. Derivatives 1a, 1b and 3b produced effects characteristic of antagonists of postsynaptic 5-HT1A receptors. Moreover, 1b exhibited features of an agonist of presynaptic 5-HT1A receptors, while 3a behaved like a partial agonist of postsynaptic 5-HT1A sites. The latter derivative may also be classified as a 5-HT2A receptor antagonist. Thus, novel potent 5-HT1A receptor ligands were successfully obtained, and the most promising compound 3a showed mixed 5-HT1A/5-HT2A receptor activity in in vitro and in vivo tests. |
| |
Keywords: | |
本文献已被 PubMed 等数据库收录! |
|