Synthesis and biological evaluation of constrained analogues of the opioid peptide H-Tyr-D-Ala-Phe-Gly-NH2 using the 4-amino-2-benzazepin-3-one scaffold.
The synthesis of conformationally restricted dipeptidic moieties 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba)-Gly ([(4S)-amino-3-oxo-1,2,4,5-tetrahydro-1H-2-benzazepin-2-yl]-acetic acid) and 8-hydroxy-4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Hba)-D-Ala ([(4S)-amino-8-hydroxy-3-oxo-1,2,4,5-tetrahydro-benzo[c]azepin-2-yl]-propionic acid) was based on a synthetic strategy that uses an oxazolidinone as an N-acyliminium precursor. Introducing these Aba scaffolds into the N-terminal tetrapeptide of dermorphin (H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2)-induced remarkable shifts in affinity and selectivity towards the opioid mu- and delta-receptors. This paper provides the synthesis and biological in vitro and in vivo evaluation of constricted analogues of the N-terminal tetrapeptide H-Tyr-D-Ala-Phe-Gly-NH2, which is the minimal subunit of dermorphin needed for dermorphin-like opiate activity.
Ballet
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Department of Organic Chemistry, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium.
Frycia
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A
Piron
J
J
Chung
N N
NN
Schiller
P W
PW
Kosson
P
P
Lipkowski
A W
AW
Tourwé
D
D
D000818:Animals; D004305:Dose-Response Relationship, Drug; D008297:Male; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis; D018847:Opioid Peptides / Q000138:chemical synthesis* / Q000737:chemistry; D011487:Protein Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013997:Time Factors
D009842:Oligopeptides; D018847:Opioid Peptides; D011957:Receptors, Opioid; C046443:tyrosyl-alanyl-delta-phenylalanyl-glycinamide