AbstractThe 5‐HT1Areceptor affinities and ionization constants of a set of 1‐arylpiperazine (4) 1,2,3,4‐tetrahydroisoquinoline (6), and ‐quinoline (7) containingN‐(ω‐arylalkyl) orN‐(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‐HT1Aligands 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 that6c, 6dand8amimicked very well the reference structures of4aand its rigid analog5. Another, more complex 1,2,3,4‐tetrahydroisoquinoline derivative3, which served as a model compound to confirm the previously reported 5‐HT1Abinding mode of derivatives1a–dand2, had the highest 5‐HT1Aaffinity (Ki= 6.7 ± 0.5 nM)