Towards multitargeted ligands as pain therapeutics: Dual ligands of the Ca_v2-1 subunit of voltage-gated calcium channel and the -opioid receptor

The synthesis and pharmacological activity of a new series of dual ligands combining activities towards the alpha 2 delta-1 subunit of voltage-gated calcium channels (Ca-v alpha 2 delta-1) and the mu-opioid receptor (MOR) as novel pain therapeutics are reported. A careful exploration of the pharmacophores related to both targets, which in principle had few common characteristics, led to the design of novel compounds exhibiting both activities. The construction of the dual ligands started from published Ca-v alpha 2 delta-1 ligands, onto which MOR ligand pharmacophoric elements were added. This exercise led to new amino-acidic substances with good affinities on both targets as well as good metabolic and physicochemical profiles and low potential for drug-drug interactions. A representative compound, (2S,4S)-4-(4-chloro-3-(((cis)-4-(dimethylamino)-4-phenylcyclohexyl)methyl)-5-fluorophenoxy)pyrrolidine-2-carboxylic acid, displayed promising analgesic activities in several in vivo pain models as well as a reduced side-effect profile in relation to morphine.