Structure‐Activity Relationship Studies of CNS Agents, Part 23 [1]) : N ‐(3‐Phenylpropyl)‐ and N ‐[3( E )‐Cinnamyl]‐1,2,3,4‐tetrahydroisoquinoline Mimic 1‐Phenylpiperazine at 5‐HT 1A 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 1,2,3,4,4a5‐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.