CHANGING THE ELECTRONIC DENSITY OF THE DISTAL PHENYL RING OF 4-ARYL-1,2,3,6-TETRAHYDROPYRIDINE DERIVATIVES TO INFLUENCE THE AFFINITY FOR 5-HT1A RECEPTORS

4-Phenyl-1,2,3,6-tetrahydropyridine(THP) moiety was shown to be favourable compared to the classical 4-phenyl-piperazine in terms of affinity for 5-HT1A receptors in a series of 4-arylpiperazine-ethyl carboxamides. The almost planar orientation found in the 4-phenyl-1,2,3,6-THP compounds appeared to be an important spatial requirement for an optimal interaction with the 5-HT1A receptor in this series. This orientation tends to stabilize the ligand binding by an edge-to-face CH-Π interaction between the phenyl ring of the 4-phenyl-1,2,3,6-THP compounds and the side chain of the Phe 6.52 residue in the binding pocket .In the present study, the electronic distribution of the distal benzene ring is modified by introducing substituents with different electronic and/or physicochemical characteristics to explore the impact on this interaction on the affinity for 5-HT1A receptors. These substituents were placed either in 4 or 3 and 5 position of the distal ring in order to avoid a sterical constraint if present in 2 or 6 position. In a quinoxalinamide series, the 3,5-dimethyl substituted analogue has the highest affinity for 5-HT1A receptors as expected. A reinforced interaction with the Phe 6.52 residue might explain this affinity but increased basicity and lipophilicity might also have a role.