Synthesis and biological activity of [Leu5]enkephalin derivatives containing D-glucose.
The synthesis of some [Leu5]enkephalin derivatives is described in which D-glucose has been linked to the opioid pentapeptide through the ester bond involving the carboxyl function at the C-terminal with C-1 or C-6 of the D-glucopyranose moiety. Enkephalin derivatives were assayed for opioid activity and found to be full agonists in bioassays based on inhibition of electrically evoked contractions of the guinea pig ileum (GPI) and of the mouse vas deferens (MVD). The obtained results suggest that the opioid activity of the tested glucoconjugates depend upon the ester bond position in the molecule. Whereas 1-O conjugate 5 was somewhat more potent than [Leu5]enkephalin in the GPI assay, the 6-O conjugates, with the exception of 1-O-benzyl derivative 11, were considerably less potent. All enkephalin derivatives were delta-receptor selective; in particular, the acetylated analog 8 was three times more delta-receptor selective than [Leu5]enkephalin.
Horvat
J
J
Department of Organic Chemistry and Biochemistry, Rudjer Bosković Institute, Zagreb, Yugoslavia.
Horvat
S
S
Lemieux
C
C
Schiller
P W
PW
D000818:Animals; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D005947:Glucose; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D011957:Receptors, Opioid / Q000187:drug effects / Q000502:physiology; D013329:Structure-Activity Relationship
D007202:Indicators and Reagents; D011957:Receptors, Opioid; D004743:Enkephalin, Leucine; D005947:Glucose