Systemic Analgesic Activity and δ-Opioid Selectivity in 1,D-Pen2,D-Pen5>enkephalin

Article abstract of DOI:10.1021/jm00082a008

The cyclic peptide <2,6-dimethyl-Tyr¹,D-Pen²,D-Pen⁵>enkephalin (2) was synthesized by solid-phase techniques and contains the optically pure unnatural amino acid 2,6-dimethyltyrosine (DMT) as a replacement for the Tyr¹ residue of 2,D-Pen⁵>enkephalin (DPDPE, 1).This structural modification resulted in a 10-fold increase in the potency of 2 at the δ-opioid receptor and a 35-fold increase in potency at the μ receptor while substantial δ receptor selectivity was maintained.In addition, 2 was 86-fold more effective than 1 at inhibiting electrically stimulated contractions of the mouse vas deferens.In the hot plate test, 2 was 7-fold more potent than 1 after intracerebroventricular administration in the mouse.While 1 was inactive following systemic administration of doses as high as 30 mg/kg, subcutaneous administration of 2 significantly inhibited writhing with an ED50 of 2.6 mg/kg.These results demonstrate that the potency and systemic activity of DPDPE are significantly increased by replacement of Tyr¹ with DMT.