Chalcone-inspired rA 1 /A 2A adenosine receptor ligands: Ring closure as an alternative to a reactive substructure.

Autor: Matthee C; Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa., Terre'Blanche G; Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa.; Pharmaceutical Chemistry, School of Pharmacy, North-West University, Potchefstroom, South Africa., Janse van Rensburg HD; Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa., Aucamp J; Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa., Legoabe LJ; Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa.
Jazyk: angličtina
Zdroj: Chemical biology & drug design [Chem Biol Drug Des] 2022 Mar; Vol. 99 (3), pp. 416-437. Date of Electronic Publication: 2021 Dec 27.
DOI: 10.1111/cbdd.13999
Abstrakt: Over the past few years, great progress has been made in the development of high-affinity adenosine A 1 and/or A 2A receptor antagonists-promising agents for the potential treatment of Parkinson's disease. Unfortunately, many of these compounds raise structure-related concerns. The present study investigated the effect of ring closures on the rA 1 /A 2A affinity of compounds containing a highly reactive α,β-unsaturated carbonyl system, hence providing insight into the potential of heterocycles to address these concerns. A total of 12 heterocyclic compounds were synthesised and evaluated in silico and in vitro. The test compounds performed well upon qualitative assessment of drug-likeness and were generally found to be free from potentially problematic fragments. Most also showed low/weak cytotoxicity. Results from radioligand binding experiments confirm that heterocycles (particularly 2-substituted 3-cyanopyridines) can replace the promiscuous α,β-unsaturated ketone functional group without compromising A 1 /A 2A affinity. Structure-activity relationships highlighted the importance of hydrogen bonds in binding to the receptors of interest. Compounds 3c (rA 1 K i  = 16 nM; rA 2A K i  = 65 nM) and 8a (rA 1 K i  = 102 nM; rA 2A K i  = 37 nM), which both act as A 1 antagonists, showed significant dual A 1 /A 2A affinity and may, therefore, inspire further investigation into heterocycles as potentially safe and potent adenosine receptor antagonists.
(© 2021 John Wiley & Sons Ltd.)
Databáze: MEDLINE
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