Endomorphin analogues with mixed μ-opioid (MOP) receptor agonism/δ-opioid (DOP) receptor antagonism and lacking β-arrestin2 recruitment activity

• Published in: Bioorganic & medicinal chemistry Vol. 22; no. 7; pp. 2208 - 2219
• Main Authors: Cai, Jun, Song, Bowen, Cai, Yunxin, Ma, Yu, Lam, Ai-leen, Magiera, Julia, Sekar, Sunder, Wyse, Bruce D., Ambo, Akihiro, Sasaki, Yusuke, Lazarus, Lawrence H., Smith, Maree T., Li, Tingyou
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.04.2014; Elsevier
• Subjects: Analgesics; Animals; Arrestins - metabolism; beta-Arrestins; Biochemistry & Molecular Biology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Colforsin - antagonists & inhibitors; Colforsin - pharmacology; Cyclic AMP - metabolism; Dmt; Endomorphin-2; Guinea Pigs; HEK293 Cells; Humans; Life Sciences & Biomedicine; Male; Mice; Molecular Structure; Oligopeptides - chemical synthesis; Oligopeptides - chemistry; Oligopeptides - pharmacology; Opioid; Pharmacology & Pharmacy; Physical Sciences; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta - antagonists & inhibitors; Receptors, Opioid, mu - agonists; Science & Technology; Opioid; Dmt; Analgesics; Endomorphin-2; TETRAPEPTIDE; AGONIST/DELTA-ANTAGONIST; EFFICACY; PHARMACOLOGICAL CHARACTERIZATION; POTENT; PEPTIDES; LIGANDS; IN-VITRO CHARACTERIZATION; VIVO ANTINOCICEPTION; DERIVATIVES
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2014.02.015

Analogues of endomorphin (Dmt-Pro-Xaa-Xaa-NH2) modified at position 4 or at positions 4 and 3, and tripeptides (Dmt-Pro-Xaa-NH2) modified at position 3, with various phenylalanine analogues (Xaa=Trp, 1-Nal, 2-Nal, Tmp, Dmp, Dmt) were synthesized and their effects on in vitro opioid activity were investigated. Most of the peptides exhibited high μ-opioid (MOP) receptor binding affinity (KiMOP=0.13–0.81nM), modest MOP-selectivity (Kiδ-opioid (DOP)/KiMOP=3.5–316), and potent functional MOP agonism (GPI, IC50=0.274–249nM) without DOP and κ-opioid (KOP) receptor agonism. Among them, compounds 7 (Dmt-Pro-Tmp-Tmp-NH2) and 9 (Dmt-Pro-1-Nal-NH2) were opioids with potent mixed MOP receptor agonism/DOP receptor antagonism and devoid of β-arrestin2 recruitment activity. They may offer a unique template for the discovery of potent analgesics that produce less respiratory depression, less gastrointestinal dysfunction and that have a lower propensity to induce tolerance and dependence compared with morphine.