NOVEL TETRAHYDRODIBENZOOXAAZECINES AS A PROBE TO DISCRIMINATE DOPAMINE D1/D5 RECEPTORS

Dopamine is a neurotransmitter that regulates several physiological functions by acting through two different receptor families named D1-like (D1 and D5) and D2-like (D2, D3 and D4). Dysfunction of the dopaminergic signal transduction is strongly related to neuropsychiatric diseases, such as schizophrenia, Parkinson’s disease, and addiction, indicating dopamine receptors as attractive therapeutic targets. Several different compounds have been developed over the last decades as ligands more or less selective toward the dopamine receptor subtypes, but the discrimination between D1 and D5 receptors is still an almost unexplored challenge.1 It has already been reported that activation of dopamine D5 receptors in the VTA may contribute to the addictive properties of cocaine.2 This observation indicates dopamine D5 antagonists as interesting potential tools for the treatment of cocaine addiction. Based on the literature, a rich panel of data concerning the topographic requirements of dopamine receptors is available. However, as above mentioned, the knowledge of the structural features of dopamine D5 selective ligands emerged during the last few years. Lehmann et al. reported the discovery of new high affinity D1-like receptors antagonists (I) with slight preference for D5 receptor subtype and indicated them as “a step toward dopamine D5 selectivity”3. Back in 2006 Nichols’ group described4 a new highly selective dopamine D1-like receptor full agonist (II) endowed with a D1-like high affinity in binding tests (8 nM) on porcine striatal preparations and a slight preference for D5 receptors in competition binding assays on cloned human receptor. Thus, we designed the synthesis of novel tetrahydrodibenzooxaazecines potentially able to bind the D1-like receptors and discriminate between D1 and D5 subtypes.