| Autor: |
Stefanucci A; Dipartimento di Farmacia, Universitá; di Chieti-Pescara 'G. d'Annunzio', Via dei Vestini 31, 66100 Chieti, Italy., Minosi P; Centro Nazionale Ricerca e Valutazione Preclinica e Clinica dei Farmaci, Istituto Superiore di Sanita, Viale Regina Elena 299, 00161 Rome, Italy., Pieretti S; Centro Nazionale Ricerca e Valutazione Preclinica e Clinica dei Farmaci, Istituto Superiore di Sanita, Viale Regina Elena 299, 00161 Rome, Italy., Tanguturi P; Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona 85012, United States., Molnar G; Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona 85012, United States., Scioli G; Dipartimento di Farmacia, Universitá; di Chieti-Pescara 'G. d'Annunzio', Via dei Vestini 31, 66100 Chieti, Italy., Marinaccio L; Dipartimento di Farmacia, Universitá; di Chieti-Pescara 'G. d'Annunzio', Via dei Vestini 31, 66100 Chieti, Italy., Della Valle A; Dipartimento di Farmacia, Universitá; di Chieti-Pescara 'G. d'Annunzio', Via dei Vestini 31, 66100 Chieti, Italy., Streicher JM; Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona 85012, United States.; Comprehensive Pain and Addiction Center, University of Arizona, Tucson, Arizona 85012, United States., Mollica A; Dipartimento di Farmacia, Universitá; di Chieti-Pescara 'G. d'Annunzio', Via dei Vestini 31, 66100 Chieti, Italy. |
| Abstrakt: |
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 Tyr 1,1' 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. |
