Synthesis and biological evaluation of leucine enkephalin turn mimetics

• Published in: Organic & biomolecular chemistry 2006-02, Vol.4 (3), p.416-423
• Main Authors: Blomberg, David, Kreye, Paul, Fowler, Chris, Brickmann, Kay, Kihlberg, Jan
• Format: Article
• Language: English
• Subjects: Animals; Biomimetic Materials - chemical synthesis; Biomimetic Materials - chemistry; Biomimetic Materials - metabolism; Biomimetic Materials - pharmacology; Biomimetic Materials/chemical synthesis/chemistry/metabolism/pharmacology; Brain - cytology; Cyclization; delta/metabolism; Enkephalin, Leucine - analogs & derivatives; Enkephalin, Leucine - chemistry; Ligands; Molecular Structure; mu/metabolism; Opioid; Rats; Receptors; Receptors, Opioid, delta - metabolism; Receptors, Opioid, mu - metabolism
• ISSN: 1477-0520; 1477-0539; 1477-0539
• DOI: 10.1039/b515618a

A cyclic Leu-enkephalin mimetic containing a 7-membered ring, and two linear analogues, has been prepared on solid phase. In the cyclic mimetic the intramolecular (1-4) hydrogen bond found in crystalline Leu-enkephalin has been replaced by an ethylene bridge. In addition, the amide bond between Tyr1 and Gly2 has been replaced by a methylene ether isostere and Gly3 has been deleted. The two linear analogues both contain the methylene ether isostere instead of the Tyr1-Gly2 amide bond and the shorter of the two lacks Gly3. The three compounds, and a beta-turn mimetic analogous to the 7-membered turn mimetic but with Gly3 included, were evaluated for specific binding to micro- and delta-opioid receptors in rat brain membranes. With the exception of the beta-turn mimetic the three other Leu-enkephalin analogues all bound with varying affinity to the micro- and delta-opioid receptors. From the results it could be concluded that Leu-enkephalin binds in a turn conformation to the opiate receptors, but that this conformation is not a (1-4) beta-turn.