Antihypertensive profile of 2-thienyl-3,4-methylenedioxybenzoylhydrazone is mediated by activation of the A2A adenosine receptor

• Published in: European journal of medicinal chemistry 2012-09, Vol.55, p.49-57
• Main Authors: Leal, Carla Moreira, Pereira, Sharlene Lopes, Kümmerle, Arthur Eugen, Leal, Daniella Moreira, Tesch, Roberta, de Sant’Anna, Carlos M.R., Fraga, Carlos Alberto M., Barreiro, Eliezer Jesus, Sudo, Roberto Takashi, Zapata-Sudo, Gisele
• Format: Article
• Language: English
• Subjects: Adenosine A2 Receptor Agonists - chemistry; Adenosine A2 Receptor Agonists - metabolism; Adenosine A2 Receptor Agonists - pharmacology; Adenosine agonist; Animals; Antihypertensive; Antihypertensive Agents - chemistry; Antihypertensive Agents - metabolism; Antihypertensive Agents - pharmacology; Biological and medical sciences; CHO Cells; Cricetinae; Cricetulus; Drug Discovery; HEK293 Cells; Humans; Hydrazones - chemistry; Hydrazones - metabolism; Hydrazones - pharmacology; LASSBio-1027; Male; Medical sciences; Miscellaneous; Molecular Docking Simulation; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - physiology; N-acylhydrazone; Pharmacology. Drug treatments; Protein Conformation; Rats; Receptor, Adenosine A2A - chemistry; Receptor, Adenosine A2A - metabolism; Receptor, Adenosine A3 - metabolism; Thiophenes - chemistry; Thiophenes - metabolism; Thiophenes - pharmacology; Time Factors; Vasodilation - drug effects; Vasodilator
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2012.06.056

Several N-acylhydrazone derivatives synthesized from safrole have been found to promote intense vasodilation and antihypertensive activity. The present work describes the synthesis and antihypertensive profile of 2-thienyl-3,4-methylenedioxybenzoylhydrazone (LASSBio-1027), a new analogue of the lead compound 3,4-methylenedioxybenzoyl-2-thienylhydrazone. Thoracic aortas from Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) were prepared for isometric tension recording. Noninvasive blood pressure measurements were made during 14 days of intraperitoneal (10 mg/kg) or oral (20 mg/kg) administration of LASSBio-1027. LASSBio-1027 exhibited partially endothelium-dependent vasorelaxant activity, which was attenuated in the presence of l-NAME, glibenclamide, or ZM 241385. LASSBio-1027 exhibited an antihypertensive effect in SHR during 14 days of intraperitoneal or oral administration, but did not induce a hypotensive effect in normotensive WKY rats. LASSBio-1027-induced vascular relaxation of aortas from WKY rats was mediated by the activation of A2A adenosine receptors. Docking studies and binding assays suggested that LASSBio-1027 has affinity for A2A and A3 adenosine receptors. This new N-acylhydrazone derivative represents a potential strategy for the treatment of arterial hypertension. [Display omitted] ► The new N-acylhydrazone derivative 2-thienyl-3,4-methylenedioxybenzoylhydrazone (LASSBio-1027) was successfully synthesized. ► LASSBio-1027 is an innovative compound and does not have structural similarity to adenosine. ► LASSBio-1027 exhibited vasodilator and antihypertensive actions. ► The molecular docking was performed in the crystal structure of A2A and A3 adenosine receptors. ► Binding assays revealed that LASSBio-1027 is a novel A2A and A3 adenosine agonist.