Therapeutic Potentials of Sarpogrelate in Cardiovascular Disease*

Saini, Harjot K.; Takeda, Nobuakira; Goyal, Ramesh K.; Kumamoto, Hideo; Arneja, Amarjit S.; Dhalla, Naranjan S.

doi:10.1111/j.1527-3466.2004.tb00130.x

Cited by 78 publications

(76 citation statements)

References 151 publications

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“…All of these processes play an important role in the pathogenesis of a wide variety of ischemic heart diseases. Sarpogrelate, a selective 5-HT 2A -receptor antagonist, has been found to have therapeutic potentials on these pathophysiological effects (5).…”

Section: -Htmentioning

confidence: 99%

Inverse Agonist Activity of Sarpogrelate, a Selective 5-HT2A-Receptor Antagonist, at the Constitutively Active Human 5-HT2A Receptor

et al. 2006

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Abstract. Mutations producing constitutively active G-protein coupled receptors have been found in the pathophysiology of several diseases, implying that inverse agonists at the constitutively active receptors may have preferred therapeutic applications. Because of the involvement of 5-HT 2A receptors in mediating many cardiovascular diseases, constitutively active mutants of the 5-HT 2A receptor may be responsible for the disease states. Thus, the purpose of the present study was to investigate the inverse agonist activity of sarpogrelate, a selective 5-HT 2A -receptor antagonist, and its active metabolite, M-1; and we compared their activities with those of other 5-HT 2A -receptor antagonists such as ritanserin, ketanserin, and cyproheptadine. Using a constitutively active mutant (C322K) of the human 5-HT 2A receptor, we demonstrated that like other 5-HT 2A -receptor antagonists, sarpogrelate acts as a potent inverse agonist by significantly reducing basal inositol phosphate levels. However, there were no significant differences between sarpogrelate and other 5-HT 2A -receptor antagonists for their inverse agonist activity. Compared with the wild type receptor, mutant receptor displayed significantly higher affinity for 5-HT and lower affinity for sarpogrelate. These results indicate that stabilization of the inactive conformation of the 5-HT 2A receptor may be a key component of the mechanism of action of sarpogrelate.

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Section: -Htmentioning

confidence: 99%

Inverse Agonist Activity of Sarpogrelate, a Selective 5-HT2A-Receptor Antagonist, at the Constitutively Active Human 5-HT2A Receptor

et al. 2006

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“…Sarpogrelate has inhibitory effects on serotonininduced platelet aggregation (Hara et al, 1991a;Nakamura et al, 1999), thrombus formation (Hara et al, 1991b;Yamashita et al, 2000), vasoconstriction, and vascular smooth muscle cell proliferation (Sharma et al, 1999), all of which are mediated by 5-HT 2A receptors, and consequently reduces the ischemic symptoms associated with peripheral arterial disease. Additionally, sarpogrelate has beneficial effects in restenosis after coronary stenting (Fujita at al., 2003;Saini et al, 2004), pulmonary hypertension (Saini et al, 2004), angina pectoris (Kinugawa et al, 2002), and diabetes mellitus (Pietraszek et al, 1993;Ogawa et al, 1999), although the precise mechanisms remain unknown. Sarpogrelate is metabolized to (6)-1-{2-[2-(3-methoxyphenil)ethyl]-phenoxy}-3-(dimethylamino)-2-propanol hydrochloride (M-1; Fig.…”

Section: Introductionmentioning

confidence: 99%

“…Sarpogrelate is metabolized to (6)-1-{2-[2-(3-methoxyphenil)ethyl]-phenoxy}-3-(dimethylamino)-2-propanol hydrochloride (M-1; Fig. 1), formed by hydrolysis from sarpogrelate (Nagatomo et al, 2004;Saini et al, 2004). The M-1 is an active sarpogrelate metabolite, which has inhibitory effects exceeding those of sarpogrelate in vitro (Pertz and Elz, 1995).…”

Section: Introductionmentioning

confidence: 99%

Selective Inhibition of Cytochrome P450 2D6 by Sarpogrelate and Its Active Metabolite, M-1, in Human Liver Microsomes

et al. 2013

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The present study was performed to evaluate the in vitro inhibitory potential of sarpogrelate and its active metabolite, M-1, on the activities of nine human cytochrome (CYP) isoforms. Using a cocktail assay, the effects of sarpogrelate on nine CYP isoforms and M-1 were measured by specific marker reactions in human liver microsomes. Sarpogrelate potently and selectively inhibited CYP2D6-mediated dextromethorphan O-demethylation with an IC 50 (K i ) value of 3.05 mM (1.24 mM), in a competitive manner. M-1 also markedly inhibited CYP2D6 activity; its inhibitory effect with an IC 50 (K i ) value of 0.201 mM (0.120 mM) was more potent than that of sarpogrelate, and was similarly potent as quinidine (K i , 0.129 mM), a well-known typical CYP2D6 inhibitor. In addition, sarpogrelate and M-1 strongly inhibited both CYP2D6-catalyzed bufuralol 19-hydroxylation and metoprolol a-hydroxylation activities. However, sarpogrelate and M-1 showed no apparent inhibition of the other following eight CYPs: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A4/5. Upon 30-minute preincubation of human liver microsomes with sarpogrelate or M-1 in the presence of NADPH, no obvious shift in IC 50 was observed in terms of inhibition of the nine CYP activities, suggesting that sarpogrelate and M-1 are not time-dependent inactivators. Sarpogrelate strongly inhibited the activity of CYP2D6 at clinically relevant concentrations in human liver microsomes. These observations suggest that sarpogrelate could have an effect on the metabolic clearance of drugs possessing CYP2D6-catalyzed metabolism as a major clearance pathway, thereby eliciting pharmacokinetic drug-drug interactions.

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“…This receptor subtype plays a central role in cognitive processes; however, it also has roles in cardiovascular processes [9]. 5-HT 2A is expressed in both coronary and pulmonary arteries, mediating smooth muscle contraction and is involved in platelet aggregation [10,21]. 5-HT 2A antagonists have been shown to lower blood pressure and this subtype is being targeted for the development of clinically efficacious anti-hypertensive agents with reduced adrenergic sideeffects [22].…”

Section: Introductionmentioning

confidence: 99%

Should We Assess the Effects of Investigational New Drugs on the Cardiovascular Relevant Serotonergic System?

Keasling¹,

Shariat‐Madar²

2016

J Clin Toxicol

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Therapeutic Potentials of Sarpogrelate in Cardiovascular Disease*

Cited by 78 publications

References 151 publications

Inverse Agonist Activity of Sarpogrelate, a Selective 5-HT2A-Receptor Antagonist, at the Constitutively Active Human 5-HT2A Receptor

Inverse Agonist Activity of Sarpogrelate, a Selective 5-HT2A-Receptor Antagonist, at the Constitutively Active Human 5-HT2A Receptor

Selective Inhibition of Cytochrome P450 2D6 by Sarpogrelate and Its Active Metabolite, M-1, in Human Liver Microsomes

Should We Assess the Effects of Investigational New Drugs on the Cardiovascular Relevant Serotonergic System?

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