Synthesis and biological evaluation of leucine enkephalin turn mimetics.
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 In the cyclic mimetic the intramolecular (1-4) hydrogen bond found in crystalline Leu-enkephalin has been replaced by an ethylene bridge. In addition, the amide bond between Tyr1 and Gly2 has been replaced by a methylene ether isostere and Gly3 has been deleted.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.
Blomberg
David
D
Organic Chemistry, Department of Chemistry, Umeå University, SE-901 87, Umeå, Sweden.
Kreye
Paul
P
Fowler
Chris
C
Brickmann
Kay
K
Kihlberg
Jan
J
D000818:Animals; D040761:Biomimetic Materials / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001921:Brain / Q000166:cytology; D003500:Cyclization; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives* / Q000737:chemistry*; D008024:Ligands; D015394:Molecular Structure; D051381:Rats; D017465:Receptors, Opioid, delta / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism
D008024:Ligands; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D004743:Enkephalin, Leucine