A new class of mu 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 mu binding affinity. In addition, it was demonstrated that mu 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.