Synthesis and opioid activity of dermorphin tetrapeptides bearing D-methionine S-oxide at position 2.
Eight new dermorphin tetrapeptides, X-Tyr-D-MetO-Phe-aa-Y (X = H, H2N = C(NH); aa = Gly, 2-aminoethanol, sarcosine; Y = NH2, NH-alkyl), were prepared and tested for opioid activity. They show dose-related naloxone-reversible opioid effects in vitro and in vivo. H-Tyr-D-MetO-Phe-Gly-NH2 (I) (guinea pig ileum IC50 = 13.6 nM; tail-flick ED50 = 1.97 pmol/mouse, icv, and 0.65 mumol/kg, sc), though less effective in the periphery, has central activities higher than those of dermorphin H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2. Following intracerebroventricular or subcutaneous administrations in mice, I is about respectively 1500 and 17 times as potent an analgesic as morphine.
Salvadori
S
S
Marastoni
M
M
Balboni
G
G
Sarto
G P
GP
Tomatis
R
R
D000701:Analgesics, Opioid / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008715:Methionine; D009119:Muscle Contraction / Q000187:drug effects; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D018847:Opioid Peptides; D013329:Structure-Activity Relationship
D000701:Analgesics, Opioid; D009842:Oligopeptides; D018847:Opioid Peptides; C030058:dermorphin; D008715:Methionine