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Drug Res (Stuttg) 2022; 72(01): 53-60
DOI: 10.1055/a-1616-0156
Original Article

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

Samuel Estrada-Soto
1   Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos, México
,
Priscila Rendón-Vallejo  
1   Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos, México
,
Rafael Villalobos-Molina
2   Unidad de Biomedicina, Facultad de Estudios Superiores-Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Estado de México, México
,
César Millán-Pacheco
1   Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos, México
,
MiguelA. Vázquez
3   Departamento de Química, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Guanajuato, México
,
Fernando Hernández-Borja
3   Departamento de Química, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Guanajuato, México
,
Emanuel Hernández-Núñez
4   Cátedra CONACyT, Departamento de Recursos del Mar, Centro de Investigación y de Estudios Avanzados del IPN, Unidad Mérida, Yucatán, Mexico
› Author Affiliations Funding Statement This study was supported by Consejo Nacional de Ciencia y Tecnología (CONACyT) Proyecto de Ciencia Básica A1-S-13540. P. Rendón-Vallejo is grateful with CONACyT for the Ph.D. fellowship grant.
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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.


Supplementary Material



Publication History

Received: 19 July 2021
Received: 20 August 2021

Accepted: 24 August 2021

Article published online:
18 October 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
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  • References

  • 1 World Health Organization. Hypertension, 2021. (Accessed 10 July 2021)
    PubMed
  • 2 Schiffrin EL. Circulatory therapeutics: use of antihypertensive agents and their effects on the vasculature. J Cell Mol Med 2010; 14: 1018-1029
    PubMedGoogle Scholar
  • 3 Zhou K, Wang X-M, Zhao Y-Z. et al. Synthesis and antihypertensive activity evaluation in spontaneously hypertensive rats of nitrendipine analogues. Med Chem Res 2011; 20: 1325-1330
    CrossrefPubMedGoogle Scholar
  • 4 Rendón-Vallejo P, Estrada-Soto S, Vázquez MA. et al. Design, synthesis and ex vivo study of the vasorelaxant activity induced by isosteric derivatives of dihydropyridines (NH→O). Lett Drug Des Discov 2016; 13: 353-359
    CrossrefPubMedGoogle Scholar
  • 5 Hernández-Abreu O, Castillo-España P, León-Rivera I, Ibarra-Barajas M, Villalobos-Molina R, Gonzalez-Christen J, Vergara-Galicia J, Estrada-Soto S. Antihypertensive and vasorelaxant effects of tilianin isolated from Agastache mexicana are mediated by NO/cGMP pathway and potassium channel opening. Biochemical Pharmacology 2009; 78: 54-61
    CrossrefPubMedGoogle Scholar
  • 6 Vergara-Galicia J, Ortiz-Andrade R, Castillo-España P. et al. Antihypertensive and vasorelaxant activities of Laelia autumnalis are mainly through calcium channel blockade. Vasc Pharmacol 2008; 49: 26-31
    CrossrefPubMedGoogle Scholar
  • 7 Rendón-Vallejo P, Hernández-Abreu O, Vergara-Galicia J. et al. Ex vivo study of the vasorelaxant activity induced by phenanthrene derivatives isolated from Maxillaria densa . J Nat Prod 2012; 75: 2241-2245
    CrossrefPubMedGoogle Scholar
  • 8 Estrada-Soto S, Rivera-Leyva JC, Ramírez-Espinosa JJ. et al. Vasorelaxant effect of Valeriana edulis subsp. procera (Valerianacea) and its mode of action as calcium channel blocker. J Pharm Pharmacol 2010; 62: 1167-1174
    CrossrefPubMedGoogle Scholar
  • 9 Vergara-Galicia J, Ortiz-Andrade R, Rivera-Leyva JC. et al. Vasorelaxant and antihypertensive effects of methanolic extract from roots of Laelia anceps are mediated by calcium channel antagonism. Fitoterapia 2010; 81: 350-357
    CrossrefPubMedGoogle Scholar
  • 10 Estrada-Soto S, González-Trujano ME, Rendón-Vallejo P. et al. Antihypertensive and vasorelaxant mode of action of the ethanol-soluble extract from Tagetes lucida Cav. aerial parts and its main bioactive metabolites. J Ethnopharmacol 2021; 266: 113399
    CrossrefPubMedGoogle Scholar
  • 11 Arias-Durán L, Estrada-Soto S, Hernández-Morales M. et al. Antihypertensive and vasorelaxant effect of leucodin and achillin isolated from Achillea millefolium through calcium channel blockade and NO production: functional ex vivo and in silico studies. J Ethnopharmacol 2021; 273: 113948
    CrossrefPubMedGoogle Scholar
  • 12 Hernández-Abreu O, Torres-Piedra M, Garcıa Jimenez S. et al. Dose-dependent antihypertensive determination and toxicological studies of tilianin isolated from Agastache mexicana . J Ethnopharmacol 2013; 146: 187-191
    CrossrefPubMedGoogle Scholar
  • 13 A Guide to The Globally Harmonized System of Classification and Labeling of Chemicals (GHS). Fourth revised Edition, United Nations, 2011
    PubMed
  • 14 Berman HM, Westbrook J, Feng Z. et al. The protein data bank. Nucleic Acids Res 2000; 28: 235-242
    CrossrefPubMedGoogle Scholar
  • 15 Zhao Y, Huang G, Wu J. et al. Molecular basis for ligand modulation of a mammalian voltage-gated Ca2+ channel. Cell 2019; 177: 1495-1506.E12
    CrossrefPubMedGoogle Scholar
  • 16 Trott O, Olson AJ. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 2010; 31: 455-461
    CrossrefPubMedGoogle Scholar
  • 17 Schrödinger LLC. Maestro. Schrödinger Release 2021-2. New York, NY
    PubMed
  • 18 Humphrey W, Dalke A, Schulten K. VMD: visual molecular dynamics. J Mol Graph 1996; 14: 33-38
    CrossrefPubMedGoogle Scholar
  • 19 Tykocki NR, Boerman EM, Jackson WF. Smooth muscle ion channels and regulation of vascular tone in resistance arteries and arterioles. Compr Physiol 2017; 7: 485-581
    CrossrefPubMedGoogle Scholar
  • 20 Flores-Flores A, Hernández-Abreu O, Rios MY. et al. Vasorelaxant mode of action of dichloromethane-soluble extract from Agastache mexicana and its main bioactive compounds. Pharm Biol 2016; 54: 2807-2813
    CrossrefPubMedGoogle Scholar
  • 21 Dolphin AC. Voltage-gated calcium channels: Their discovery, function and importance as drug targets. Brain Neurosci Adv 2018; 2: 1-8
    CrossrefPubMedGoogle Scholar
  • 22 Zamponi GW, Striessnig J, Koschak A. et al. The physiology, pathology, and pharmacology of voltage-gated calcium channels and their future therapeutic potential. Pharmacol Rev 2015; 67: 821-870
    CrossrefPubMedGoogle Scholar
  • 23 Hernández F, Sánchez A, Rendón-Vallejo P. et al. Synthesis, ex vivo and in silico studies of 3-cyano-2-pyridone derivatives with vasorelaxant activity. Eur J Med Chem 2013; 70: 669-676
    CrossrefPubMedGoogle Scholar
  • 24 Gao S, Yan N. Structural basis of the modulation of the voltage-gated calcium ion channel Cav1.1 by dihydropyridine compounds. Angew. Chem Int Ed Engl 2021; 60: 3131-3137
    CrossrefPubMedGoogle Scholar
  • 25 Fan JS, Palade P. Effects of FPL 64176 on Ca2+ transients in voltage-clamped rat ventricular myocytes. Br J Pharmacol 2002; 135: 1495-1504
    CrossrefPubMedGoogle Scholar
  • 26 Marom M, Hagalili Y, Sebag A. et al. Conformational changes induced in voltage-gated calcium channel Cav1.2 by BayK 8644 or FPL64176 modify the kinetics of secretion independently of Ca2+ influx. J Biol Chem 2010; 285: 6996-7005
    CrossrefPubMedGoogle Scholar
  • 27 Grundy JS, Eliot LA, Foster RT. Extrahepatic first-pass metabolism of nifedipine in the rat. Biopharm Drug Dispos 1997; 18: 509-522
    CrossrefPubMedGoogle Scholar
  • 28 Katzung BG. Basic and Clinical Pharmacology: Section III, Antihypertensive Drugs. 14th Edition. McGraw Hill; New York: 2018
    Google Scholar
  • 29 Lomize MA, Pogozheva ID, Joo H, Mosberg HI, Lomize AL. OPM database and PPM web server: resources for positioning of proteins in membranes. Nucleic Acids Research 2012; 40: D370-D376
    CrossrefPubMedGoogle Scholar