4,6-Di(heteroaryl)-2-(N-methylpiperazino)pyrimidines as new, potent 5-HT2A receptor ligands: A verification of the topographic model

A series of new 4,6-di(heteroaryl)pyrimidines containing an N-methylpiperazino group (6-13) or an ethylenediamine chain (15-20) in position 2 were synthesized and their 5-HT1A and 5-HT2A receptor affinities were determined. It was shown that the substituent effects on the 5-HT2A affinity are additive and could be described quantitatively, In a behavioral model it was also demonstrated that 6-11 are 5-HT2A receptor antagonists. The molecular modelling results suggested that the distances between the basic nitrogen atom and the two aromatic centers (d(1) = 5.2-8.4 Angstrom, d(2) = 5.7-8.5 Angstrom, and d(3) = 4.6-7.3 Angstrom) define the molecular topography of the 5-HT2A receptor antagonists under study.