The Synthesis And Vasodilatory Activity Of Rutaecarpine Analogs

Hypertension is one of the most threatened diseases with rapid growing morbidity rates. At present, the majority of anti-hypertension drugs are concerned about inhibiting the production or effect of the endogenous pressors. Meanwhile, it is another important pathway to find out the promotors of endogenous vasodilators.Vanilloid receptor subtype 1 (VR1), a signal integration in the peripheral nociceptor terminal, plays an important role in transducing thermal and inflammatory pain. Activating VR1 makes peripheral sensory neuron release potent vasodilator neuropeptides, including Calcitonin gene-related peptide (CGRP). CGRP, the most potent vasodilator plays an important role in the initiation, progression and maintenance of hypertension. Researches are focus on the substances which can increase the CGRP synthesis and release.Rutaecarpine is the major alkaloidal component of Wu-Chu-Yu, a well known Chinese herbal drug. The compound has been shown to relax vascular smooth muscle and decrease the blood pressure effectively. It has been reported that rutaecarpine causes the vasodilatory, positive inotropic and cardioprotective effects by stimulation of CGRP synthesis and release via activation of VR1.In this study, 23 rutaecarpine analogs were designed and synthesized. The structures of these compounds were confirmed by MS,¹H and ¹³CNMR spectroscopy. Then, the vesodilatory effect of theses compounds were screened by rat aorta ring experiment. One of them, 10-methyl-rutaecarpine exhibited similar effect with rutaecarpine. Further experiments shows its depressor and vesodilatory activity are related to the stimulation of CGRP synthesis and release via activation of VR1.The vesodilatory effect result shows that the 14-N atom of rutaecarpine might be the key site to the activity. The 5-carbonyl might make lower contribution to the effect. And simple substitute in A ring and E ring would not enhance the vesodilatory effect either unless in proper position with proper group.In conclusion, a series of rutaecarpine analogs were systematically synthesized. The vesodilatory effect of these compounds were evaluated and the structure-activity relationship between rutaecarpine and the vesodilatory effect was elucidate for the first time. The results suggested a new direction of valuable VR1 agonist as antihypertension drugs.