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 w ell as two morpholine derivatives (8a, 8b) were determined. It was sho wn that some tetrahydroisoquinoline (6c, 6d) and morpholine (8a) deriv atives 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 molecul ar modelling studies it was also demonstrated that 6c, 6d and 8a mimic ked very well the reference structures of 4a and its rigid analog 5. A nother, more complex 1,2,3,4-tetrahydroisoquinoline derivative 3, whic h 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 affini ty (K-i = 6.7 +/- 0.5 nM) of all the investigated compounds.