Naphthalene and 2,3-dihydrobenzo[b][1,4]dioxine derivatives with extended side chains as new scaffolds of CB2-selective ligands

Abstract

Herein, we report the synthesis of naphthalene, dihydrobenzodioxine and fluorene derivatives with extended side chains and their biological evaluation as ligands of CB₁ and CB₂ receptors. Compounds 6a and 18b showed K_i values in the submicromolar range and relatively high selectivity toward CB₂. Active compounds represent new scaffolds with such type of activity. Moreover, a multiple XED-based field templates model has been constructed for the activity interpretation of some of the synthesised compounds. The reported ligands can serve as a template to develop new CB₂ ligands with enhanced potency and selectivity, and the computational model can be applied for SAR interpretation and/or structure optimization of any other CB₂-selective ligand(s).