TY - JOUR
T1 - Design of Analgesic Trivalent Peptides with Low Withdrawal Symptoms
T2 - Probing the Antinociceptive Profile of Novel Linear and Cyclic Peptides as Opioid Pan Ligands
AU - Stefanucci, Azzurra
AU - Minosi, Paola
AU - Pieretti, Stefano
AU - Tanguturi, Parthasaradhireddy
AU - Molnar, Gabriella
AU - Scioli, Giuseppe
AU - Marinaccio, Lorenza
AU - Della Valle, Alice
AU - Streicher, John M.
AU - Mollica, Adriano
N1 - Funding Information:
This work was supported by R01DA052340 to J.M.S. J.M.S. has an equity stake in Teleport Pharmaceuticals, LLC, and Botanical Results, LLC; no company products or interests were tested in this study. This work was also supported by Istituto Superiore di Sanità, Rome, Italy, via the intramural research supporting fund to P.S. and P.M. The authors have no other relevant conflicts of interest to declare.
Publisher Copyright:
© 2023 American Chemical Society.
PY - 2023/2/1
Y1 - 2023/2/1
N2 - 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 in vitro and in vivo 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 Tyr1,1′ by Dmt (2,5-dimethyltyrosine) in the linear biphalin analogue AM94 and cyclic analogue MACE4 resulted in two new compounds (namely, MJ2 and MJ5) endowed with improved KOR/MOR/DOR binding affinity. Both compounds showed a strong antinociceptive profile in in vivo models of nociception, allodynia, and hyperalgesia via the tail flick, hot plate, and formalin tests after intracerebroventricular and subcutaneous administration. One of these ligands, MJ2, was also tested in tolerance and dependence studies, exhibiting very little withdrawal symptoms.
AB - 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 in vitro and in vivo 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 Tyr1,1′ by Dmt (2,5-dimethyltyrosine) in the linear biphalin analogue AM94 and cyclic analogue MACE4 resulted in two new compounds (namely, MJ2 and MJ5) endowed with improved KOR/MOR/DOR binding affinity. Both compounds showed a strong antinociceptive profile in in vivo models of nociception, allodynia, and hyperalgesia via the tail flick, hot plate, and formalin tests after intracerebroventricular and subcutaneous administration. One of these ligands, MJ2, was also tested in tolerance and dependence studies, exhibiting very little withdrawal symptoms.
KW - biphalin
KW - nociception
KW - opioid
KW - pan ligands
KW - peptides
KW - withdrawal
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U2 - 10.1021/acschemneuro.3c00005
DO - 10.1021/acschemneuro.3c00005
M3 - Article
C2 - 36651179
AN - SCOPUS:85146614337
SN - 1948-7193
VL - 14
SP - 506
EP - 515
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
IS - 3
ER -