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.
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.
Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, PL 31-343 Kraków, Poland.
Maria H
MH
Paluchowska
Maria J
MJ
Mokrosz
Sijka
S
Charakchieva-Minol
Beata
B
Duszyńska
Aneta
A
Kozioł
Anna
A
Wesołowska
Katarzyna
K
Stachowicz
Ewa
E
Chojnacka-Wójcik
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001667:Binding, Competitive; D001831:Body Temperature / Q000187:drug effects; D015259:Dopamine Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D015394:Molecular Structure; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D018490:Serotonin Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D013997:Time Factors
D015259:Dopamine Agents; D010879:Piperazines; D044402:Receptor, Serotonin, 5-HT2A; D017448:Receptors, Dopamine D2; D018490:Serotonin Agents; D044005:Tetrahydroisoquinolines; D044282:Receptor, Serotonin, 5-HT1A