TESTING D2-LIKE RECEPTOR AFFINITY AND SELECTIVITY WITH NOVEL IMIDAZOLINE DERIVATIVES

The bioversatility of the imidazoline ring exemplified by its presence in nicotinic, α1- and α2-adrenergic, I1 and I2 imidazoline ligands and MAO inhibitors suggests that novel derivatives may also target the dopamine D2-like receptor family. Our molecules were built on a common pharmacophore characterized by the presence of an aromatic nucleus that was meta or para substituted with a methoxy or hydroxy group; an ethylene, oxymethylene or vinyl bridge and an N-benzyl or N-phenethyl substituted imidazoline ring. Competition binding experimentsusing [3H]N-methylspiperonein human D2, D3 and D4 receptorsstably expressed in HEK293 cells were used to assessthe affinities of this series of analogues.Preliminary results show: 1) only the derivatives containingan ethylene bridge were able to displace the radioligandwhereas an oxymethylene or vinylic chain was unfavourable. 2)The lenght of the N-substituent played a critica roleon D2-like receptor binding affinities. While the N-benzyl derivatives had poor affinity for all three receptor subtypes, the N-phenethyl derivativesshowed significant D4-affinity. 3) The presence of a methoxy group,particularly in the meta-position,appeared to favor D4 receptors much more than the hydroxy group. In contrast, the para hydroxy substituent gave higher affinity at D3 receptors. 4) Finally, the presence of the cathecol nucleus in the aromatic area eliminated any affinityfor the D2-like receptors. In conclusion, the imidazoline nucleus can be a suitable carrier for D2-like ligands and in particular , modification at the 2-substituent may play a role in D2-family subtype selectivity.