New scaffolds in the development of Mu opioid-receptor ligands

A new class of μ selective receptor antagonists has been developed using a combinatorial approach based on previously reported Dmt-Tic dipeptide ligands. Modified tetrahydroisoquinoline (Tiq) residues were reacted with different electrophiles in order to create novel molecules that would mimic the original dipeptide. A specific class of thioureas bearing basic pyrrolidine residues were shown to give good binding affinities. Further alkylation of the pyrrolidine ring with benzyl derivatives also proved to increase the μ binding affinity. In addition, it was demonstrated that μ binding was enhanced by the presence of polar groups around the benzyl ring having hydrogen-bonding character (donor/acceptor). This new class of ligands represents a novel scaffold in the development of opioid analogues.