Synthesis of mixed MOR/KOR efficacy cyclic opioid peptide analogs with antinociceptive activity after systemic administration

European Journal of Medicinal Chemistry
Renata PerlikowskaAnna Janecka

Abstract

Cyclic pentapeptide Tyr-c[D-Lys-Phe-Phe-Asp]NH2, based on the structure of endomorphin-2 (EM-2), which shows high affinity to the μ-opioid receptor (MOR) and a very strong antinociceptive activity in mice was used as a parent compound for the structure-activity relationship studies. In this report we synthesized analogs of a general sequence Dmt-c[D-Lys-Xaa-Yaa-Asp]NH2, with D-1- or D-2-naphthyl-3-alanine (D-1-Nal or D-2-Nal) in positions 3 or 4. In our earlier papers we have indicated that replacing a phenylalanine residue by the more extended aromatic system of naphthylalanines may result in increased bioactivities of linear analogs. The data obtained here showed that only cyclopeptides modified in position 4 retained the sub-nanomolar MOR and nanomolar κ-opioid receptor (KOR) affinity, similar but not better than that of a parent cyclopeptide. In the in vivo mouse hot-plate test, the most potent analog, Dmt-c[D-Lys-Phe-D-1-Nal-Asp]NH2, exhibited higher than EM-2 but slightly lower than the cyclic parent peptide antinociceptive activity after peripheral (ip) and also central administration (icv). Conformational analyses in a biomimetic environment and molecular docking studies disclosed the structural determinants responsible...Continue Reading

References

Aug 15, 1986·Science·A PfeifferH M Emrich
Mar 19, 1993·Journal of Medicinal Chemistry·T YamazakiP W Schiller
Dec 20, 1999·Chemical & Pharmaceutical Bulletin·Y SasakiY Yamamoto
Mar 23, 2004·Current Pharmaceutical Design·D L DeHaven-Hudkins, R E Dolle
Feb 22, 2005·Current Medicinal Chemistry·Anna Janecka, Rafal Kruszynski
Jul 2, 2005·Expert Opinion on Investigational Drugs·A Barber, R Gottschlich
Dec 16, 2005·The AAPS Journal·Irina D PogozhevaHenry I Mosberg
Aug 22, 2006·Current Medicinal Chemistry·Maria KatsaraVasso Apostolopoulos
Jan 29, 2008·Current Medicinal Chemistry·Anna JaneckaJakub Fichna
Apr 10, 2008·The FEBS Journal·Luca GentilucciAndrea Bedini
Feb 3, 2009·Naunyn-Schmiedeberg's Archives of Pharmacology·Valeria CamardaGirolamo Calo
Dec 10, 2009·Peptides·Renata PerlikowskaAnna Janecka
Dec 29, 2009·Journal of Molecular Graphics & Modelling·Attila Borics, Géza Tóth
May 22, 2010·ChemMedChem·Attila KeresztesGéza Tóth
Jul 6, 2010·Bioorganic & Medicinal Chemistry·Lorella PasquinucciGiuseppe Ronsisvalle
Oct 11, 2011·Peptides·Richard J Bodnar
Feb 27, 2013·Journal of Medicinal Chemistry·Benjamin M GreedyStephen M Husbands
Dec 3, 2014·Bioorganic & Medicinal Chemistry·Justyna PiekielnaAnna Janecka
May 26, 2015·ACS Medicinal Chemistry Letters·Justyna PiekielnaAnna Janecka

❮ Previous
Next ❯

Citations

Dec 26, 2016·Peptides·Richard J Bodnar
Mar 21, 2017·Bioorganic & Medicinal Chemistry·Anna Adamska-BartłomiejczykAnna Janecka
Feb 29, 2020·Chemical Science·Huy N HoangDavid P Fairlie
Sep 23, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Arijit SarkarAnna Janecka
Dec 8, 2020·Frontiers in Chemistry·Alaa TalhamiChaim Gilon
Jun 5, 2020·Peptides·Karol WtorekAnna Janecka

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.