Structure-Activity Relationship Studies of 6α- and 6β-Indolylacetamidonaltrexamine Derivatives as Bitopic Mu Opioid Receptor Modulators and Elaboration of the "Message-Address Concept" To Comprehend Their Functional Conversion

ACS Chemical Neuroscience
Samuel ObengYan Zhang

Abstract

Structure-activity relationship (SAR) studies of numerous opioid ligands have shown that introduction of a methyl or ethyl group on the tertiary amino group at position 17 of the epoxymorphinan skeleton generally results in a mu opioid receptor (MOR) agonist while introduction of a cyclopropylmethyl group typically leads to an antagonist. Furthermore, it has been shown that introduction of heterocyclic ring systems at position 6 can favor antagonism. However, it was reported that 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(2'-indolyl)acetamido]morphinan (INTA), which bears a cyclopropylmethyl group at position 17 and an indole ring at position 6, acted as a MOR agonist. We herein report a SAR study on INTA with a series of its complementary derivatives to understand how introduction of an indole moiety with α or β linkage at position 6 of the epoxymorphinan skeleton may influence ligand function. Interestingly, one of INTA derivatives, compound 15 (NAN) was identified as a MOR antagonist both in vitro and in vivo. Molecular modeling studies revealed that INTA and NAN may interact with different domains of the MOR allosteric binding site. In addition, INTA may interact with W293 and N150 residues found in the orthosteri...Continue Reading

References

Nov 1, 1976·Proceedings of the National Academy of Sciences of the United States of America·A P FeinbergS H Snyder
Jun 9, 1977·Nature·J A LordH W Kosterlitz
Mar 1, 1990·Journal of Medicinal Chemistry·D M Zimmerman, J D Leander
Jul 1, 1973·Proceedings of the National Academy of Sciences of the United States of America·E J SimonI Edelman
Mar 9, 1973·Science·C B Pert, S H Snyder
Sep 1, 1965·Journal of Medicinal Chemistry·P S Portoghese
Oct 1, 1981·Proceedings of the National Academy of Sciences of the United States of America·C Chavkin, A Goldstein
May 2, 1983·Life Sciences·T J Coderre, G B Rollman
Feb 1, 1995·Protein Engineering·A C WallaceJ M Thornton
Feb 1, 1996·Journal of Molecular Graphics·W HumphreyK Schulten
Apr 1, 1997·Biophysical Journal·S IzrailevK Schulten
Apr 4, 1997·Journal of Molecular Biology·G JonesR Taylor
Jun 3, 2000·Annual Review of Pharmacology and Toxicology·P Y LawH H Loh
Aug 23, 2002·Proceedings of the National Academy of Sciences of the United States of America·Bryan L RothRichard B Rothman
Dec 1, 1954·The Journal of Pharmacy and Pharmacology·A H BECKETT, A F CASY
Jan 6, 2004·Medicinal Research Reviews·Masakatsu Eguchi
Mar 19, 2005·Chembiochem : a European Journal of Chemical Biology·Yan ZhangPhilip S Portoghese
May 4, 2005·Proceedings of the National Academy of Sciences of the United States of America·Hyung-June Woo, Benoît Roux
Oct 14, 2005·Journal of Computational Chemistry·James C PhillipsKlaus Schulten
Feb 21, 2006·Naunyn-Schmiedeberg's Archives of Pharmacology·Markus KathmannEberhard Schlicker
Dec 28, 2010·Biochemical Pharmacology·Neil T BurfordAndrew Alt
Mar 23, 2012·Nature·Aashish ManglikSébastien Granier
Nov 13, 2012·Annual Review of Pharmacology and Toxicology·Vsevolod KatritchRaymond C Stevens
Nov 14, 2012·Journal of Chemical Information and Modeling·K VanommeslaegheA D MacKerell
Nov 14, 2012·Journal of Chemical Information and Modeling·K Vanommeslaeghe, A D MacKerell
Jun 12, 2013·Proceedings of the National Academy of Sciences of the United States of America·Neil T BurfordAndrew Alt

❮ Previous
Next ❯

Citations

Dec 14, 2019·Current Topics in Medicinal Chemistry·Bethany A ReineckeYan Zhang
Apr 9, 2021·Peptides·Richard J Bodnar
May 7, 2021·Journal of Medicinal Chemistry·Samuel ObengChristopher R McCurdy

❮ 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.