Development of a novel class of brain penetrant ligands endowed with high affinity and selectivity for dopamine D4 receptors

Dopamine is a catecholamine neurotransmitter involved in a great variety of physiological functions, through the interaction with five different G-protein-coupled receptors, namely D1-D5 receptors (D1R-D5R). Among dopamine receptors, the D4R subtype has recently emerged as a potential target for the treatment of widespread diseases, such as eating disorders, drug addiction and cancer. For these reasons, it has garnered considerable interest. Classical D4R ligands are characterized by a common pharmacophore, consisting of a lipophilic moiety linked by a spacer to a piperidine or piperazine basic function and an aromatic terminal. It has recently been demonstrated that the known M1 muscarinic bitopic agonist 77-LH-28-1 also behaved as a potent D4R ligand and showed an unexpected D4 selectivity over D2 and D3 subtypes. Interestingly, the structure of 77-LH-28-1 differs from those of other known selective D4R ligands, that are characterized by the presence of a properly substituted aromatic group at position 4 of the piperidine ring. On the contrary, 77-LH-28-1 bears a butyl aliphatic chain. 77-LH-28-1 being the first example of D4R selective ligand with a unique structural feature, an extensive structure-activity relationship study has been undertaken to evaluate the importance of the butyl aliphatic chain for the interaction with D4R. From a preliminary study, potent, selective and brain penetrant D4R antagonists were identified. The promising results prompt us to further investigate the structural requirements of 77-LH-28-1 favoring the selective interaction with the D4R.