Synthesis and Structure-Affinity Relationships of Spirocyclic Benzopyrans with Exocyclic Amino Moiety

Journal of Medicinal Chemistry
Elisabeth KronenbergBernhard Wünsch

Abstract

σ1 and/or σ2 receptors play a crucial role in pathological conditions such as pain, neurodegenerative disorders, and cancer. A set of spirocyclic cyclohexanes with diverse O-heterocycles and amino moieties (general structure III) was prepared and pharmacologically evaluated. In structure-activity relationships studies, the σ1 receptor affinity and σ1:σ2 selectivity were correlated with the stereochemistry, the kind and substitution pattern of the O-heterocycle, and the substituents at the exocyclic amino moiety. cis-configured 2-benzopyran cis-11b bearing a methoxy group and a tertiary cyclohexylmethylamino moiety showed the highest σ1 affinity ( Ki = 1.9 nM) of this series of compounds. In a Ca2+ influx assay, cis-11b behaved as a σ1 antagonist. cis-11b reveals high selectivity over σ2 and opioid receptors. The interactions of the novel σ1 ligands were analyzed on the molecular level using the recently reported X-ray crystal structure of the σ1 receptor protein. The protonated amino moiety forms a persistent salt bridge with E172. The spiro[benzopyran-1,1'-cyclohexane] scaffold and the cyclohexylmethyl moiety occupy two hydrophobic pockets. Exchange of the N-cyclohexylmethyl moiety by a benzyl group led unexpectedly to potent ...Continue Reading

References

Mar 1, 1992·Trends in Pharmacological Sciences·R QuirionD P Taylor
Apr 27, 1988·European Journal of Pharmacology·J SharkeyM J Kuhar
Nov 18, 2000·European Journal of Pharmacology·W Hong, L L Werling
Jan 11, 2002·Journal of Medicinal Chemistry·Christoph A Maier, Bernhard Wünsch
Jul 21, 2004·Journal of Computational Chemistry·Eric F PettersenThomas E Ferrin
Nov 18, 2004·Pharmacopsychiatry·W E MüllerC Gentsch
Nov 1, 2006·Current Pharmaceutical Design·Kenji Hashimoto, Kiichi Ishiwata
Jul 22, 2008·Investigative Ophthalmology & Visual Science·Kissaou T TchedreThomas Yorio
Apr 29, 2009·Journal of Computational Chemistry·Garrett M MorrisArthur J Olson
Dec 22, 2009·Organic & Biomolecular Chemistry·Daniel KrachtBernhard Wünsch
Feb 19, 2010·The Journal of Pharmacology and Experimental Therapeutics·Ikhlas S AhmedRolf J Craven
Oct 23, 2010·Bioorganic & Medicinal Chemistry·Ashutosh BanerjeeBernhard Wünsch
Sep 28, 2012·Journal of Medicinal Chemistry·Jens KöhlerBernhard Wünsch
Mar 7, 2013·Bioorganic & Medicinal Chemistry·Christina MeyerBernhard Wünsch
Apr 16, 2013·Bioorganic & Medicinal Chemistry Letters·Erik LauriniSabrina Pricl
Jun 6, 2013·Journal of Medicinal Chemistry·Robert H MachWilliam G Hawkins
Nov 10, 2011·ACS Medicinal Chemistry Letters·Erik LauriniSabrina Pricl
Jul 13, 2014·European Journal of Medicinal Chemistry·Kengo MiyataBernhard Wünsch
Dec 22, 2014·European Journal of Medicinal Chemistry·Daniele ZampieriMaria Grazia Mamolo
Apr 5, 2016·Nature·Hayden R SchmidtAndrew C Kruse
May 10, 2016·Journal of Medicinal Chemistry·Frauke WeberBernhard Wünsch
Jan 5, 2017·Expert Opinion on Therapeutic Patents·Simona CollinaAnna Tesei
Jun 1, 2017·Proceedings of the National Academy of Sciences of the United States of America·Assaf AlonAndrew C Kruse

❮ Previous
Next ❯

Citations

Jun 3, 2021·International Journal of Molecular Sciences·Héctor Torres-GómezBernhard Wünsch
Jun 28, 2021·European Journal of Medicinal Chemistry·Tao ZhuangYin Chen

❮ 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.