des-Formylflustrabromine (dFBr): A Structure-Activity Study on Its Ability To Potentiate the Action of Acetylcholine at α4β2 Nicotinic Acetylcholine Receptors

ACS Chemical Neuroscience
Malgorzata DukatRichard A Glennon

Abstract

The naturally occurring indole alkaloid des-formylflustrabromine (dFBr; 1) is one of the first agents shown to act as a selective positive allosteric modulator (PAM) at α4β2 nicotinic acetylcholine receptors (nAChRs). We previously deconstructed this agent to determine which of its structural features contribute to its actions and have identified an agent that might serve as the basis for a " working pharmacophore". Here, we elaborate the dFBr (1; EC50 = 0.2 μM) structure to identify how various structural modifications impact its actions. Electrophysiological studies with Xenopus laevis oocytes identified several compounds with dFBr-like potency and one, the 5-bromo analogue of 1 (i.e., 5-bromo dFBr; 25; EC50 = 0.4 μM), with more than twice the efficacy of 1 as a PAM at α4β2 nAChRs.

References

Nov 1, 1973·Journal of Medicinal Chemistry·C HanschE J Lien
Dec 23, 2003·Journal of Neuroscience Methods·P R JoshiM K Schulte
Jan 16, 2007·Organic Letters·Thomas LindelPetra Böhrer
Jun 19, 2007·Trends in Pharmacological Sciences·Hans RollemaKathryn E Williams
Jun 22, 2007·Bioorganic & Medicinal Chemistry·Bernadette HugonMichelle Prudhomme
Jul 3, 2007·Bioorganic & Medicinal Chemistry Letters·Jin-Sung KimRichard A Glennon
Mar 5, 2008·Journal of the American Chemical Society·Leyla CelikBirgit Schiøtt
Jun 7, 2011·Organic & Biomolecular Chemistry·Thomas B ParsonsRichard S Grainger
Sep 13, 2011·Journal of Medicinal Chemistry·Nadezhda GermanRichard A Glennon
Oct 5, 2011·Pharmacological Reviews·Maryka Quik, Susan Wonnacott
Jun 27, 2012·European Journal of Pharmacology·Maegan M WeltzinMarvin K Schulte
Jun 6, 2014·Journal of Medicinal Chemistry·Li-Fang YuAlan P Kozikowski
Nov 20, 2016·The Journal of Biological Chemistry·Constanza AlcainoIsabel Bermudez

❮ Previous
Next ❯

Citations


❮ 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.