Structure-activity relationship studies of CNS agents. Part 10(1): 1-Aryl-2-[3-(4-aryl-1-piperazinyl)propyl]-1,4-dihydro-3(2H)-isoquino linones: two modes of the interaction with the 5-HT1A receptor site.
The synthesis and 5-HT1A and 5-HT2 receptor affinities of 1-aryl-2-[3-(4-aryl-1-piperazinyl)propyl]-1,4-dihydro-3(2H)- isoquinolinones 7-28 are reported. The two derivatives 7 and 13 were the most potent 5-HT1A ligands (Ki 1.72 +/- 0.07 and 2.75 +/- 0.59 nM, respectively) of all the investigated compounds. It has been found that the effect of the substituent in the 1-arylpiperazine portion is opposite to the observed in simple 1-arylpiperazine. The molecular modelling results indicate that the investigated derivatives may interact with 5-HT1A sites in two different ways: as ordinary 4-substituted 1-arylpiperazines, or in such a manner that the aryl substituent at position 1 of the 3(2H)-isoquinolinone moiety and N-4 piperazine atom mimics remarkably well the bioactive conformation of simple 1-arylpiperazines.
Department of Medicinal Chemistry, Polish Academy of Sciences, Kraków.
J L
JL
Mokrosz
A J
AJ
Bojarski
M
M
Maćkowiak
Z
Z
Bielecka
J
J
Boksa
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000493:pharmacokinetics; D000818:Animals; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D007650:Ketanserin / Q000493:pharmacokinetics; D008958:Models, Molecular; D010879:Piperazines / Q000494:pharmacology; D011619:Psychotropic Drugs / Q000494:pharmacology; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013329:Structure-Activity Relationship
D007546:Isoquinolines; D010879:Piperazines; D011619:Psychotropic Drugs; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D007650:Ketanserin; C031503:phenylpiperazine; C015068:1-(3-chlorophenyl)piperazine