Synthesis of 2-chloropurine ribosides with chiral amino acid amides at C6 and their evaluation as A(1) adenosine receptor agonists

• Published in: Bioorganic chemistry Vol. 126
• Main Authors: Berzina, Maria Ya, Eletskaya, Barbara Z., Kayushin, Alexei L., Dorofeeva, Elena, Lutonina, Olga, Fateev, Ilya, Paramonov, Alexander S., Kostromina, Maria A., Zayats, Evgeniy A., Abramchik, Yulia A., Maltsev, Dmitriy, Naumenko, Ludmila, Taran, Alena S., Yakovlev, Dmitry S., Spasov, Alexander A., Miroshnikov, Anatoly, Esipov, Roman S., Konstantinova, Irina D.
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier 01.09.2022
• Subjects: Biochemistry & Molecular Biology; Chemistry; Chemistry, Organic; Life Sciences & Biomedicine; Physical Sciences; Science & Technology; Intraocular Pressure; ANALOGS; Adenosine Derivative; NUCLEOSIDES; Adenosine Receptor Agonists; INTRAOCULAR-PRESSURE; GUANOSINE; RETINAL ISCHEMIA; FUNCTIONALIZATION; PHARMACOLOGY; BIOLOGICAL ACTIVITY; ANTAGONISTS; DERIVATIVES
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2022.105878

A series of purine ribonucleosides bearing chiral amino acid amides at the C6 position of 2-chloropurine was synthesized. Molecular docking of the synthesized analogs of 2-chloroadenosine by their affinity for A(1) adenosine receptors (A(1)ARs) was conducted. The investigation of A(1)AR stimulating activity of synthesized nucleosides was carried out in a model of an isolated mouse atrium. We have shown that derivatives with tyrosine, valine, and serine residues exhibit the properties of A(1)AR partial agonists. Animal experiments in the open field test have shown that these compounds have different profiles of psychoactive action. These nucleosides have an ophthalmic hypotensive effect and reduce intraocular pressure in a manner slightly inferior to that of timolol and brimonidine. The synthesized nucleosides can be the basis for further design and synthesis of new A(1)AR agonists.