Structure-activity relationship studies of CNS agents. Part 29. N-Methylpiperazino-substituted derivatives of quinazoline, phthalazine and quinoline as novel α1, 5-HT(1A) and 5-HT(2A) receptor ligands

Article abstract of DOI:10.1016/S0223-5234(97)86176-4

New N-methylpiperazino-substituted quinazolines 8 and 9, phthalazine 13, and quinoline 19 have been synthesized. The receptor binding profiles (α₁, 5-HT(1A), 5-HT(2A)) of these compounds and their analogs (7-22) have been determined. It has been demonstrated that orientation of a local dipole moment of the heteroaromatic ring system affects both the α₁ and 5-HT(2A) affinity of the investigated class of ligands. Distortion of the coplanar unfused heteroaromatic ring system results in a decreased 5-HT(2A) affinity. 4-(4-Methylpiperazino)-2-(2-thienyl)quinoline 18 is the most active and selective α₁ ligand (K(i) = 4.9 nM) with a much lower affinity for 5-HT(1A) (K(i) = 3420 nM) and 5-HT(2A) (K(i) = 211 nM) receptors.