Structure-Activity Relationship Studies of CNS Agents, Part 23[1]):N-(3-Phenylpropyl)- andN-[3(E)-Cinnamyl]-1,2,3,4-tetrahydroisoquinoline Mimic 1-Phenylpiperazine at 5-HT1A Receptors

The 5-HT 1A receptor affinities and ionization constants of a set of 1-arylpiperazine (4) 1,2,3,4-tetrahydroisoquinoline (6), and -quinoline (7) containing N-(ω-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-HT 1A 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-HT 1A binding mode of derivatives 1a-d and 2, had the highest 5-HT 1A affinity (K i = 6.7 ± 0.5 nM) of all the investigated compounds