Discovery of Vasorelaxant Alkaloids for Treatment of Hypertension

 

Leaves of Ficus Schwarzii (Photo taken from Krishnan, P.; Lee, F.-K.; Yap, V. A.; Low, Y.-Y.; Kam, T.-S.; Yong, K.-T.; Ting, K.-N.; Lim, K.-H. J. Nat. Prod. 2020, 83 (1), 152–158.)

High blood pressure, also called hypertension is a medical condition characterized by the systolic blood pressure of  ≥140 mm Hg and the diastolic blood pressure of ≥ 90 mm Hg.¹ In 2000, about 26% of the adult population worldwide had hypertension and this number is projected to increase to about 29% by 2025.² It is associated with several medical conditions such as stroke, renal failure and cardiovascular diseases.³ Although antihypertensive medications are widely available, a segment of patients still suffers from resistant hypertension, a condition in which blood pressure remains above goal (140/90 mm Hg). This, despite the patient is concurrently taking three or more antihypertensive drugs of different classes for treatment.⁴ While scientific studies in resistant hypertension are numerous, no single medication has been specifically developed for the treatment of resistant hypertension.⁵ Moreover, the uses of drug combinations in the treatment of hypertension are often restricted by adverse effects associated with the particular class of antihypertensive drug.⁶ The current situation, therefore, shows the urgent need to discover molecules that act via novel mechanism of action to address the resistant hypertension issue.

A series of alkaloids has been recently isolated from the leaves of Ficus Schwarzii, a previously uninvestigated Ficus species in Malaysia.⁷ These alkaloids named schwarzinicines A – G represent the first examples of 1,4-diarylbutanoid-phenethylamine conjugates. Their chemical structures are determined by chemical analysis techniques of mass spectroscopy, 1D and 2D NMR spectroscopy. The vasorelaxant activities of schwarzinicines A−D were then evaluated in drug-precontracted rat isolated aortic rings. Schwarzinicines A−D were found to exhibit pronounced vasorelaxation effects in the aortic tissues in a concentration-dependent manner. The maximum relaxation magnitude produced by all the four compounds was significantly greater than that of dobutamine, a known phenylalkylamine vasorelaxant agent. It is worth to note that the potency of all the compounds tested was comparable. Thus, it suggested that minor variations in substituents or substitution patterns on the aryl ring C have little effect on their activities.

While more studies are being carried out on the schwarzinicine alkaloids and they will be reported in due course, it is promising for these vasorelaxant alkaloids to be developed into useful therapeutic agents in the hope to treat resistant hypertension.

 

Words by: Dr. Lee Fong Kai, Faculty of Pharmacy

References

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2.      Kearney, P. M.; Whelton, M.; Reynolds, K.; Muntner, P.; Whelton, P. K.; He, J. Lancet 2005, 365 (9455), 217–223.

3.      Messerli, F. H.; Williams, B.; Ritz, E. Lancet (London, England) 2007, 370 (9587), 591–603.

4.      Sarafidis, P. A.; Bakris, G. L. J. Am. Coll. Cardiol. 2008, 52 (22), 1749–1757.

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6.      Gradman, A. H.; Basile, J. N.; Carter, B. L.; Bakris, G. L. J. Am. Soc. Hypertens. 2010, 4 (2), 90–98.

7.      Krishnan, P.; Lee, F.-K.; Yap, V. A.; Low, Y.-Y.; Kam, T.-S.; Yong, K.-T.; Ting, K.-N.; Lim, K.-H. J. Nat. Prod. 2020, 83 (1), 152–158.