STRUCTURE-ACTIVITY RELATIONSHIP STUDIES OF CNS AGENTS .10. ERAZINYL)PROPYL]-1,4-DIHYDRO-3(2H)-ISOQUINOLINONES - 2 MODES OF THE INTERACTION WITH THE 5-HT(1A) RECEPTOR-SITE

The synthesis and 5-HT1A and 5-HT2 receptor affinities of erazinyl)pro pyl]-1,4-dihydro-3(2H)-isoquinolinones 7-28 are reported. The two deri vatives 7 and 13 were the most potent 5-HT1A ligands (K(i) 1.72 +/- 0. 07 and 2.75 +/- 0.59 nM, respectively) of all the investigated compoun ds. It has been found that the effect of the substituent in the 1-aryl piperazine portion is opposite to the observed in simple 1-arylpiperar zine. The molecular modelling results indicate that the investigated d erivatives may interact with 5-HT1A sites in two different ways: as or dinary 4-substituted 1-arylpiperazines, or in such a manner that the a ryl substituent at position 1 of the 3(2 H)-isoquinolinone moiety and N-4 piperazine atom mimics remarkably well the bioactive conformation of simple 1-arylpiperazines.