TRANS-2-ARYL-N,N-DIPROPYLCYCLOPROPYLAMINES - SYNTHESIS AND INTERACTIONS WITH 5-HT1A RECEPTORS

Twelve N,N-dipropyl-substituted derivatives of trans-2-arylcyclopropyl amine have been prepared and assayed for their ability to displace [H- 3]-8-OH-DPAT from rat brain 5-HT1A receptors. The new derivatives incl ude phenyl (7a), bromo- (7b) and fluorophenyl (7c-e), 2-methoxy-5-fluo rophenyl (7h), and 2-hydroxy-5-fluorophenyl (7I) as well as trifluorom ethylphenyl (7f) and 2,3-dichlorophenyl (7g) analogues. In the present series of compounds, electron-withdrawing substituents in the phenyl ring appear to decrease the affinity for 5-HT1A receptors. In contrast , electron-rich aryl groups, such as 2- or 3-thienyl (7j and 7k, respe ctively), provide compounds with high affinity. The additional bulk pr oduced by the aromatic moiety in the 2-benzothienyl derivative 7i appe ars to be detrimental to 5-HT1A receptor affinity. The racemic mixture s of the interesting 7j and 7I were resolved into the enantiomers; 7j and 7I exhibited a high enantiomeric 5-HT1A receptor affinity ratio (7 5-fold and 100-fold, respectively). The enantiomers of 7j and 7I were evaluated in vivo by use of biochemical and behavioral tests in rats. Compound (LR,2R)-7j behaved as a partial agonist whereas (1R,2S)-7I ap peared as an efficacious 5-HT1A receptor agonist, stimulating both aut oreceptors and postsynaptic receptors.