STRUCTURE-ACTIVITY RELATIONSHIP STUDIES OF CNS AGENTS .23. N-(3-PHENYLPROPYL)-1,2,3,4-TETRAHYDRO-ISOQUINOLINE AND N-[(E)-CINNAMYL]-1,2,3,4-TETRAHYDRO-ISOQUINOLINE MIMIC 1-PHENYLPIPERAZINE AT 5-HT1A RECEPTORS

The 5-HT1A receptor affinities and ionization constants of a set of 1-arylpiperazine (4) 1,2,3,4-tetrahydroisoquinoline (6), and -quinoline (7) containing N-(omega-arylalkyl) or N-(E)-cinnamyl substituents as well as two morpholine derivatives (8a, 8b) were determined. It was shown that some tetrahydroisoquinoline (6c, 6d) and morpholine (8a) derivatives were 5-HT1A ligands equipotentto 1-phenylpiperazine (4a) and 1,2,3,4,4a,5-hexahydropyrazino[1,2-a]indole (5). On the basis of molecular modelling studies it was also demonstrated that 6c, 6d and 8a mimicked very well the reference structures of 4a and its rigid analog 5. Another, more complex 1,2,3,4-tetrahydroisoquinoline derivative 3, which served as a model compound to confirm the previously reported 5-HT1A binding mode of derivatives 1a-d and 2, had the highest 5-HT1A affinity (K-i = 6.7 +/- 0.5 nM) of all the investigated compounds.