The discovery of a potent and selective pyrazolo-[2,3-e]-[1,2,4]-triazine cannabinoid type 2 receptor agonist

Michael Moir; Samuel Lane; Andrew P Montgomery; David Hibbs; Mark Connor; Michael Kassiou

doi:10.1016/j.ejmech.2020.113087

The discovery of a potent and selective pyrazolo-[2,3-e]-[1,2,4]-triazine cannabinoid type 2 receptor agonist

Eur J Med Chem. 2021 Jan 15:210:113087. doi: 10.1016/j.ejmech.2020.113087. Epub 2020 Dec 5.

Authors

Michael Moir¹, Samuel Lane², Andrew P Montgomery¹, David Hibbs³, Mark Connor⁴, Michael Kassiou⁵

Affiliations

¹ School of Chemistry, The University of Sydney, NSW, 2006, Australia.
² Faculty of Health Sciences, The University of Sydney, NSW, 2006, Australia.
³ Sydney Pharmacy School, The University of Sydney, NSW, 2006, Australia.
⁴ Department of Biomedical Sciences, Macquarie University, NSW, 2109, Australia.
⁵ School of Chemistry, The University of Sydney, NSW, 2006, Australia. Electronic address: [email protected].

PMID: 33321261
DOI: 10.1016/j.ejmech.2020.113087

Abstract

The development of selective CB₂ receptor agonists is a promising therapeutic approach for the treatment of inflammatory diseases, without CB₁ receptor mediated psychoactive side effects. Preliminary structure-activity relationship studies on pyrazoylidene benzamide agonists revealed the -ylidene benzamide moiety was crucial for functional activity at the CB₂ receptor. A small library of compounds with varying linkage moieties between the pyrazole and substituted phenyl group has culminated in the discovery of a potent and selective pyrazolo-[2,3-e]-[1,2,4]-triazine agonist 19 (CB₂R EC₅₀ = 19 nM, CB₁R EC₅₀ > 10 μM). Docking studies have revealed key structural features of the linkage group that are important for potent functional activity.

Keywords: CB(2)R selective; Cannabinoid; Docking; Pyrazolotriazine; Structure-activity relationship study; Synthesis.

MeSH terms

Cannabinoid Receptor Agonists / chemical synthesis
Cannabinoid Receptor Agonists / chemistry
Cannabinoid Receptor Agonists / pharmacology*
Dose-Response Relationship, Drug
Drug Discovery*
Humans
Molecular Structure
Receptor, Cannabinoid, CB2 / agonists*
Structure-Activity Relationship

Substances

Cannabinoid Receptor Agonists
Receptor, Cannabinoid, CB2