Jerzy L. Mokrosz

Structure-activity relationship studies of CNS agents. Part 29. N-Methylpiperazino-substituted derivatives of quinazoline, phthalazine and quinoline as novel α1, 5-HT1A and 5-HT2A receptor ligands

Summary New N -methylpiperazino-substituted quinazolines 8 and 9 , phthalazine 13 , and quinoline 19 have been synthesized. The receptor binding profiles (α 1 , 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 α 1 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 α 1 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.

Structure-activity relationship studies of CNS agents-XVII. Spiro[piperidine-4′,1-(1,2,3,4-tetrahydro-β-carboline)] as a probe defining the extended topographic model of 5-HT1A receptors

Abstract Spiro[piperidine-4′,1-(1,2,3,4-tetrahydro-β-carboline)] ( 10 ), its derivatives 11–15 and its analogs 16 and 17 were examined as ligands of serotonin 5-HT 1A receptors. It was shown that compounds 12 and 14 had essentially the same 5-HT 1A affinity as 1-phenylpiperazine and its rigid analog 7 , whereas there were substantial differences in the steric arrangement of their crucial pharmacophores, i.e. aromatic and protonation centers. On the basis of the existing models and using the (+)-LSD structure as a template, a new, extended three-point topographic model of 5-HT 1A receptors has been proposed.

Structure and spectral properties of β-carbolines. 8. Mechanism of the Pictet-Spengler cyclization: An MNDO approach☆

Abstract Formation of 1,2,3,4-tetrahydro-β-carboline in the Pictet-Spengler reaction was studied using an MNDO approach. It was shown that the formation of the spiroindolenine intermediate 6 was a thermodynamically favourable process compared with a direct C-2 pathway ( 5 ). However, since the rearrangement of 6 into 5 involves a high energy transition state, the direct C-2 pathway seems to be a key step in the Pictet-Spengler cyclization.