Design of Analgesic Trivalent Peptides with Low Withdrawal Symptoms: Probing the Antinociceptive Profile of Novel Linear and Cyclic Peptides As Opioid Pan Ligands

The discovery of efficacious and safe analgesics with reduced side effects is the foremost challenge in the pain field. In this work, we report the and evaluation of linear and cyclic analogues of biphalin with the aim to complete the series of structural modifications previously applied in the development of opioid peptides incorporating a xylene bridge. Replacement of Tyr by Dmt (2,5-dimethyltyrosine) in the linear biphalin analogue and cyclic analogue resulted in two new compounds (namely, and ) endowed with improved KOR/MOR/DOR binding affinity. Both compounds showed a strong antinociceptive profile in models of nociception, allodynia, and hyperalgesia via the tail flick, hot plate, and formalin tests after intracerebroventricular and subcutaneous administration. One of these ligands, , was also tested in tolerance and dependence studies, exhibiting very little withdrawal symptoms.