Structure-activity relationship studies of CNS agents .29. N-methylpiperazino-substituted derivatives of quinazoline, phthalazine and quinoline as novel alpha(1), 5-HT1A and 5-HT2A receptor ligands

New N-methylpiperazino-substituted quinazolines 8 and 9, phthalazine 13, and quinoline 19 have been synthesized. The receptor binding profiles (alpha(1), 5-HT1A, 5-HT2A) 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 alpha(1) and 5-HT2A affinity of the investigated class of ligands. Distortion of the coplanar unfused heteroaromatic ring system results in a decreased 5-HT2A affinity. 4-(4-Methylpiperazino)-2-(2-thienyl)quinoline 18 is the most active and selective alpha(1) ligand (K-i = 4.9 nM) with a much lower affinity for 5-HT1A (K-i = 3420 nM) and 5-HT2A (K-i = 211 nM) receptors.