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1.
ACS Chem Neurosci ; 10(1): 201-208, 2019 01 16.
Article in English | MEDLINE | ID: mdl-30179508

ABSTRACT

A series of fentanyl analogues modified at the phenyl group of the phenethyl with alkyl and/or hydroxyl and alkoxy, and the phenyl group in the anilido moiety replaced with benzyl or substituted benzyl, were synthesized. The in vitro opioid receptor functional activity of these compounds was evaluated by assessment of their ability to modulate forskolin-stimulated cAMP accumulation and by their ability to induce ß-arrestin2 recruitment. Compound 12 is a potent µ-opioid (MOP) receptor agonist, a potent κ-opioid (KOP) receptor antagonist with weak ß-arrestin2 recruitment activity. Compounds 10 and 11 are potent MOP receptor agonists with weak δ-opioid (DOP) receptor antagonist activity and moderate KOP receptor antagonist activity as well as weak ß-arrestin2 recruitment activity at the MOP receptor. These compounds are promising leads for discovery of potent opioid analgesics with reduced side effects relative to clinically available strong opioid analgesics.


Subject(s)
Analgesics, Opioid/metabolism , Fentanyl/analogs & derivatives , Fentanyl/metabolism , Receptors, Opioid/metabolism , Analgesics, Opioid/chemical synthesis , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical/methods , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/analogs & derivatives , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/chemical synthesis , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/metabolism , Fentanyl/chemical synthesis , HEK293 Cells , Humans , Narcotic Antagonists/chemical synthesis , Narcotic Antagonists/metabolism , Protein Binding/physiology
2.
Eur J Med Chem ; 68: 167-77, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23974016

ABSTRACT

Endomorphin-2 [Tyr-Pro-Phe-Phe-NH2] and DAMGO [Tyr-D-Ala-Gly-(N-Me)Phe-Gly-ol] are natural (EM2) and synthetic (DAMGO) opioid peptides both selective for µ opioid receptor with high analgesic activity. In this work we report synthesis, in vitro and in vivo biological evaluation of five new hybrid EM2/DAMGO analogues, with the aim to obtain compounds with high affinity at µ-opioid receptor, high activity in animal nociception tests (hot plate and tail flick) and improved enzymatic stability. Double N-methylation on both Phe residues and C-terminal ethanolamide led to analogue 6e, which possesses a good in vitro µ affinity (Kiµ=34 nM), combined with a remarkable in vivo antinociceptive activity.


Subject(s)
Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/chemical synthesis , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/pharmacology , Oligopeptides/chemical synthesis , Oligopeptides/pharmacology , Receptors, Opioid, mu/agonists , Analgesics, Opioid/chemical synthesis , Analgesics, Opioid/chemistry , Analgesics, Opioid/pharmacology , Animals , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/chemistry , Enzyme Stability/drug effects , Guinea Pigs , Humans , Male , Molecular Structure , Oligopeptides/chemistry , Rats , Rats, Wistar
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