6-Amino-3-Methyl-4-(2-nitrophenyl)-1,4-Dihydropyrano[2,3-c]Pyrazole-5-Carbonitrile Shows Antihypertensive and Vasorelaxant Action via Calcium Channel Blockade

Abstract

Several 4H-pyran derivatives were designed and synthesized previously as vasorelaxant agents for potential antihypertensive drugs. In this context, the objective of the present investigation was to determine the functional mechanism of vasorelaxant action of 6-amino-3-methyl-4-(2-nitrophenyl)-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (1) and its in vivo antihypertensive effect. Thus, compound 1 showed significant vasorelaxant action on isolated aorta rat rings pre-contracted with serotonin or noradrenaline, and the effect was not endothelium-dependent. Compound 1 induced a significant relaxant effect when aortic rings were contracted with KCl (80 mM), indicating that the main mechanism of action is related to L-type calcium channel blockade. Last was corroborated since compound 1 induced a significant concentration-dependent lowering of contraction provoked by cumulative CaCl₂ adding. Moreover, compound 1 was capable to block the contraction induced by FPL 64176, a specific L-type calcium channel agonist, in a concentration-dependent manner. On the other hand, docking studies revealed that compound 1 interacts on two possible sites of the L-type calcium channel and it had better affinity energy (−7.80+/−0.00 kcal/mol on the best poses) than nifedipine (−6.86+/−0.14 kcal/mol). Finally, compound 1 (50 mg/kg) showed significant antihypertensive activity, lowering the systolic and diastolic blood pressure on spontaneously hypertensive rats (SHR) without modifying heart rate.

Key words

4H-pyran derivative - antihypertensive - calcium channel blockade - dihydropyridines - nifedipine - vasorelaxant

^**Taken in part from the PhD thesis of P. Rendón-Vallejo.

Publication History

Received: 19 July 2021
Received: 20 August 2021

Accepted: 24 August 2021

Article published online:
18 October 2021

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