1,4-DIOXANE NUCLEUS AS A SUITABLE SCAFFOLD FOR NOVEL D2-LIKE RECEPTOR LIGANDS

The dopamine receptor system plays a key role in numerous neuropsychiatric and neurological disorders. Dopamine receptors are classified into two subfamilies, D1-like and D2-like. The D1-like subfamily is comprised of the D1 and D5 receptors that are coupled to stimulatory G-protein α subunits (Gs/olf ) and activate adenylyl cyclase. In contrast, the D2, D3, and D4 receptors, members of the D2-like subfamily, are coupled to inhibitory G protein α subunits (Gi/o), thus inhibiting adenylyl cyclase as well as modulating other effector pathways. Recently, the dopamine D2-like receptor subtypes (D2, D3, D4) have been studied to delineate the molecular mechanisms responsible for the reinforcing effects of psychostimulants. In this pursuit, selective D3 receptor blockade may antagonize drug reward and/or reinforcement. The 1,4-Dioxane nucleus has been demonstrated to be a suitable scaffold for binding different receptor systems through appropriate molecular decoration. In fact, this nucleus is present in muscarinic agonists and antagonists, selective α1D-adrenergic antagonists, potent 5-HT1A serotoninergic receptor full agonists and anticancer agents. In a recent investigation, competition binding experiments using [3H]N-methylspiperone in human D2, D3 or D4 receptors stably expressed in HEK 293 cells provided data for compounds 1-3 suggesting that the diphenyl-substituted 1,4-dioxane-methylamine fragment might be a suitable scaffold to confer dopaminergic receptor activity. The aim of this study was to synthesize novel 1,4-dioxane-analogues, as high affinity and selective D3 receptor ligands. The diphenyl substituted 1,4-dioxane nucleus was coupled with the N-(4-(4-(2,3-dichloro)-piperazine-1-yl)butyl)carboxamide or N-(3-fluoro or 3-hydroxy-4-(4-(2,3-dichloro)-piperazine-1-yl)butyl)carboxamides fragments that have previously been shown to play a crucial role in increasing selectivity towards the D3 dopaminergic receptor compared to the D2 and D4 receptors. Herein we describe the synthesis of a novel series of hybrid molecules and preliminary binding data at the D2-like receptor subtypes.