Design and synthesis of long-chain arylpiperazines with mixed affinity for serotonin transporter (SERT) and 5-HT(1A) receptor.
A new generation of antidepressant agents could be represented by compounds with mixed activity as serotonin transporter (SERT) inhibitors and 5-HT(1A) receptor antagonists. We report here on the synthesis and evaluation of SERT and 5-HT(1A) receptor affinity of long-chain arylpiperazines obtained either by modifying 6-nitroquipazine into a long-chain arylpiperazine or by inserting a modified 6-nitroquipazine moiety or other structures endowed with SERT affinity into a long-chain arylpiperazine with 5-HT(1A) affinity. Among the compounds studied, 2-[4-(2-methoxyphenyl)piperazin-1-yl]-N-(6-nitro-2-quinolyl)ethylamine (21) and 1-(5-bromo-1,2,3,4-tetrahydronaphthalen-1-yl)-3-[4-(2-methoxyphenyl)-piperazin-1-yl]-1-propanone (24) showed good affinity values for SERT and 5-HT(1A) receptors (SERT: K(i) (inhibition constant)=71.8 and 62.8 nM; 5-HT(1A)K(i)=14.2 and 0.82 nM, respectively).
Perrone
Roberto
R
Dipartimento Farmaco-Chimico, Università degli Studi di Bari, via Orabona 4, 70125 Bari, Italy. perrone@farmchim.uniba.it
Berardi
Francesco
F
Colabufo
Nicola A
NA
Lacivita
Enza
E
Larizza
Carmela
C
Leopoldo
Marcello
M
Tortorella
Vincenzo
V
D000818:Animals; D001667:Binding, Competitive; D015195:Drug Design; D005021:Ethylamines / Q000138:chemical synthesis / Q000494:pharmacology; D006168:Guinea Pigs; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009281:Naphthalenes / Q000138:chemical synthesis / Q000494:pharmacology; D010879:Piperazines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011407:Propane / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011814:Quipazine / Q000031:analogs & derivatives / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D012701:Serotonin / Q000494:pharmacology; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014316:Tritium
C509495:1-(5-bromo-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(4-(2-methoxyphenyl)-piperazin-1-yl)-1-propanone; C509494:2-(4-(2-methoxyphenyl)piperazin-1-yl)-N-(6-nitro-2-quinolyl)ethyamine; D005021:Ethylamines; D009281:Naphthalenes; D010879:Piperazines; D011725:Pyridines; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D017366:Serotonin Receptor Agonists; D014316:Tritium; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D011814:Quipazine; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; C031227:6-nitroquipazine; D011407:Propane