Identification of high-potency neuropeptide Y analogues through systematic lactamization

Journal of Medicinal Chemistry
D A KirbyJean E Rivier

Abstract

In the pursuit of potent analogues of neuropeptide Y (NPY) that are selective for the Y1 receptor subtype, two lactam bridge scans of a centrally truncated parent compound were synthesized. A single lactam bridge (gamma-carboxyl of Glu to epsilon-amino of Lys) extending from residues i to i + 3 or i to i + 4 of the proposed alpha-helical region (residues 25-31 of NPY) was introduced in des-AA7-24[Gly6]NPY. Cyclogues (contraction of cyclic analogues), which were approximately one-half the size of native NPY, were initially screened for binding affinity at two discrete NPY receptor types using human neuroblastoma cell membranes, SK-N-MC and SK-N-BE2. Exploitation of the subtle differences present on each receptor type allowed for the identification of cyclogues which bound specifically to Y1 receptors with increased affinity when compared to the corresponding linear parent analogue, while one short Y1 specific cyclogue, des-AA2,3,5,7-24cyclo-(26/29)[Gly6,Glu26,Lys2 9,Pro34]NPY, bound with Ki = 16 nM. Other cyclogues showed distinct preference for Y2 receptors and bound in the low-nanomolar range. Functionally, the compounds inhibited the norepinephrine-stimulated accumulation of cAMP indicating that all acted as agonists with var...Continue Reading

References

May 15, 1992·European Journal of Biochemistry·D F MierkeG Jung
Jul 1, 1992·Proceedings of the National Academy of Sciences of the United States of America·H HerzogL A Selbie
Jan 1, 1990·Proceedings of the National Academy of Sciences of the United States of America·J FuhlendorffT W Schwartz
Jun 1, 1990·Journal of Medicinal Chemistry·M ForestA Fournier
Mar 13, 1989·FEBS Letters·S P SheikhT W Schwartz
Jun 1, 1989·Proceedings of the National Academy of Sciences of the United States of America·J L KrstenanskyL R McLean
Oct 27, 1995·Journal of Medicinal Chemistry·D A KirbyJ E Rivier
Nov 7, 1995·Proceedings of the National Academy of Sciences of the United States of America·J GulyasJ Rivier
Aug 11, 1995·Molecular and Cellular Endocrinology·M SautelP Walker
Mar 1, 1995·Pharmacology & Therapeutics·J G WettsteinJ L Junien
Dec 27, 1994·European Journal of Pharmacology·K RudolfH N Doods
Apr 3, 1995·FEBS Letters·C Serradeil-Le GalP de Cointet
Jun 1, 1993·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·M HeiligK T Britton
May 14, 1996·Proceedings of the National Academy of Sciences of the United States of America·I LundellD Larhammar

❮ Previous
Next ❯

Citations

Oct 4, 2011·Journal of Medicinal Chemistry·Keith K KhooRaymond S Norton
Aug 1, 1997·European Journal of Biochemistry·B RistA G Beck-Sickinger
Jul 3, 2013·Marine Drugs·Ryan M BradyRaymond S Norton
Apr 30, 2010·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Raymond S Norton
Jan 16, 2021·Angewandte Chemie·Søren ØstergaardBirgitte S Wulff
May 17, 2002·Journal of Medicinal Chemistry·Shenggen YaoRaymond S Norton
Nov 7, 2018·Journal of Medicinal Chemistry·Søren ØstergaardBirgitte S Wulff

❮ 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.