Synthesis and in vitro opioid activity profiles of DALDA analogues

The tetrapeptide DALDA (H-Tyr- d-Arg-Phe-Lys-NH 2) is a polar and selective μ agonist showing poor penetration of the placental and blood–brain barriers. In an effort to enhance the potency of DALDA, analogues containing 2′,6′-dimethyltyrosine (Dmt), N,2′,6′-trimethyltyrosine (Tmt), 2′-methyltyrosin...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2000-10, Vol.35 (10), p.895-901
Main Authors: Schiller, Peter W, Nguyen, Thi M.-D, Berezowska, Irena, Dupuis, Sébastien, Weltrowska, Grazyna, Chung, Nga N, Lemieux, Carole
Format: Article
Language:English
Subjects:
[Dmt 1]DALDA
Analgesics - chemical synthesis
Analgesics - chemistry
Analgesics - metabolism
Analgesics - pharmacology
Animals
Biological and medical sciences
Brain - drug effects
Brain - metabolism
DALDA
DALDA analogues
GPI and MVD bioassays
Guinea Pigs
Ileum - drug effects
Ileum - metabolism
In Vitro Techniques
Medical sciences
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Oligopeptides - chemical synthesis
Oligopeptides - chemistry
Oligopeptides - metabolism
Oligopeptides - pharmacology
opioid receptor binding assays
opoid peptides
Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems
Pharmacology. Drug treatments
Rats
Receptors, Opioid, mu - agonists
Receptors, Opioid, mu - metabolism
μ opioid agonists
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Summary:The tetrapeptide DALDA (H-Tyr- d-Arg-Phe-Lys-NH 2) is a polar and selective μ agonist showing poor penetration of the placental and blood–brain barriers. In an effort to enhance the potency of DALDA, analogues containing 2′,6′-dimethyltyrosine (Dmt), N,2′,6′-trimethyltyrosine (Tmt), 2′-methyltyrosine (Mmt) or 2′-hydroxy,6′-methyltyrosine (Hmt) in place of Tyr 1, or Orn or α,γ-diaminobutyric acid (A 2bu) in place of Lys 4, were synthesized. All compounds displayed high μ receptor selectivity in the rat and guinea pig brain membrane binding assays and most of them were more potent μ agonists than DALDA in the μ receptor-representative guinea pig ileum assay, with [Dmt 1]DALDA showing the highest potency. Because of its extraordinary μ agonist potency, high μ selectivity, polar character (charge of 3+) and metabolic stability, [Dmt 1]DALDA has potential for use in obstetrical or peripheral analgesia.
ISSN:0223-5234
1768-3254
DOI:10.1016/S0223-5234(00)01171-5