Novel Dopamine Receptor Ligands Bearing Imidazoline Nucleus.

The potential clinical usefulness of centrally acting Dopamine (DA) receptor agonists and antagonists has stimulated intense research on new dopaminergic agents, mainly because several pathological conditions such as Parkinson’s disease (PD), schizophrenia and hyperprolactinemia have been linked to a dysfunction of dopaminergic transmission. (1) Molecular cloning has established the existence of two families of DA receptors: D1-like (D1 and D5) and D2-like (D2, D3 and D4) on the basis of their ability to activate or inhibit the enzyme adenylate cyclase, respectively. (2) Several studies of ours demonstrated the versatility of the imidazoline ring. In fact, depending on the particular kind of substituent inserted in position 2 of imidazoline nucleus, it was possible to modulate the ligand profile, both with regard to different systems (2-Adrenergic Receptors, Imidazoline Binding Sites, Nicotinic and Muscarinic Receptors, MAO-A inhibitors) (3) and inside the same system, with resultant enhanced subtype selectivity. Imidazoline compounds have not been yet explored as DA receptor ligands, but the well known prototype of I2 receptor ligands 2-(benzofuran-2-yl)-4,5-dihydro-1H-imidazole (2-BFI) behaved also as DA indirect agonist and displayed a 47 M binding to the DA D2 receptors. (4) Therefore, with the aim to improve the DA D2-like receptor binding affinity, novel molecules 1a-i based on the 2-BFI scaffold were designed and synthesized. The substituents R1-R3 were chosen among those reported to be beneficial for the binding of DA D2-like receptor agonists. Preliminary pharmacological results will be discussed.