Peptides containing dialkylglycines

Abstract

Three novel peptide analogues containing a residue of the hindered amino acid dibenzylglycine (Dbg) were prepared. Although [Glp6, Dbg7]‐substance P‐(6–11) possessed no substance P agonist or antagonist activity, [Dbg4, Leu5]‐enkephalinamide was 8.4 times as potent as [Leu5]‐enkephalinamide in isolated tissue assays for opioid activity, and proved highly δ‐selective (300‐fold). [N,N‐Di‐allyl Tyr1, Dbg4, Leu5]‐enkephalinamide was a moderately potent opioid antagonist, but showed little μ or δ selectivity. Dbg residues were incorporated using 2‐trifluoromethyl‐4,4‐dibenzyl‐oxazolin‐5‐one. Problems were experienced in coupling even dipeptides to peptides containing amino‐terminal Dbg, and the ‘encapsulation’ of any dialkylglycine residue at the centre of a tripeptide before further coupling offered the best synthetic strategy for future work in such analogues.

Exploring the Backbone of Enkephalins To Adjust Their Pharmacological Profile for the δ-Opioid Receptor

“…This result is consistent with previous research showing that the replacement of L-Phe 4 with D-Phe 4 in Leu 5 -enkephalin strongly reduces its affinity and activity for DOPR (17,18). In fact, it is known that the phenyl side chain of the L-Phe 4 residue of Leu 5 -enkephalin is critical for its biological activity (17) and that Leu 5 -enkephalin containing the hindered amino acid dibenzylglycine (Dbg) at position 4 is a potent DOPR agonist (53). Based on this information, we concluded that compound 3 contains L-Phe 4 while compound 5 contains D-Phe 4 .…”