Faculty of Science: N-phenethyl-1-phenyl-pentan-3-amine, (FK70) is a Novel Synthetic Compound with Vasorelaxant Activity in Rat Aorta

22 February 2017 (Venue : BA05)

Name : Kayatri Govindaraju - Department of Biomedical Sciences

Chairperson : Dr Pan Yan

Evaluator : Dr Pan Yan

Title : N-phenethyl-1-phenyl-pentan-3-amine, (FK70) is a Novel Synthetic Compound with Vasorelaxant Activity in Rat Aorta

Abstract : In an earlier project, Schwarzinicine A (Sch A), a phenylethylamine alkaloid, was isolated from the leaves of Ficus Schwarzii. Sch A is shown to have similar vasorelaxation effect as dobutamine and isoprenaline in the rat aorta. N-phenethyl-1-phenyl-pentan-3-amine, (FK70) is a novel compound synthesised by Lee Fong Kai (Pharmacy) based on the pharmacophore of Sch A to serve as an alternative compound to study the mechanism of action of these novel compounds. Both FK70 and Sch A are phenylethylamines with a secondary amine and aromatic phenyl rings. The differences in terms of their structures are, FK70 has 2 aromatic phenyl rings compared to Sch A which has 3 aromatic phenyl rings and 3,4 di-methoxy substituents are absent in FK70.
The main aim of this study is to examine the mechanism of action of FK70 as a vasorelaxant in the rat isolated aortic rings. Standard organ bath set up was used to test different protocols. The aortic rings were obtained from 6-8 weeks old male Sprague Dawley rats. Our data showed that FK70 elicits similar relaxant effect as Sch A with no significant difference in the maximal relaxation, Emax values of 104.3 ± 17.6 % (n=5) and 117.9 ± 15.9 % (n=4) respectively. The effects of FK70 on aorta pre-constricted with different contractile agents were studied using phenylephrine (0.1µM), potassium chloride (KCl) (60mM) and U46619 (0.1µM). Aortic tissues that were pre-constricted with KCl and phenylephrine exhibited comparable relaxation tone of Emax 128.92 ± 8.0 % (n=7) and 117.67 ± 25.0 % (n=5) respectively while the response with U46619 was the lowest 73.11 ± 20.8 % (n=5). This shows that the relaxation properties of FK70 are affected by the different mechanism of contractions induced by different contractile agents. To investigate the possible involvement of the endothelium, FK70 was added cumulatively on endothelium denuded aortic rings (E-) that were pre-constricted with phenylephrine. Removal of endothelium did not affect the relaxation effect of FK70 (E-: Emax = 124.5 ± 32.7 %, (n=6) vs E+: Emax = 118.2 ± 27.8 % (n=7)). To confirm that FK70 did not behave like an alpha-adrenoceptor antagonist, rauwolscine and prazosin (both alpha adrenoceptor antagonists) were incubated in the bath set up when conducting the concentration response curve of FK70. We found that FK70 relaxation effect is not affected in the presence of these antagonists. In summary, our present results show that FK70 relaxes the aorta not via the blockage of alpha-adrenoceptors nor dependent on endothelium-derived vasorelaxation factors. The next step of the project will be centred on investigating the putative relaxation mechanisms of FK70 in normotensive and spontaneously hypertensive rats (SHR), then to perform Western blot study to find out the specific protein e.g TRP channels involved in the aorta to provide rational basis for drug design and finally the toxicity assay of FK70 will be performed using Caenorhabditis Elegans (C.Elegans) to examine the toxicity of FK70 on the uninfected worms.