Syntheses and platelet aggregation inhibitory and antithrombotic properties of [2-[(.omega.-Aminoalkoxy)phenyl]benzenes

Kikumoto, Ryoji; Hara, Hiroto; Ninomiya, Kunihiro; Osakabe, Masanori; Sugano, Mamoru; Fukami, Hironobu; Tamao, Yoshikuni

doi:10.1021/jm00168a043

Cited by 51 publications

(29 citation statements)

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“…Kasho et al (15) demonstrated that 5-HT increased the production of type 4 collagen by cultured human mesangial cells through 5-HT 2A receptor, which was mediated by activation of protein kinase C and subsequent increase in transforming growth factor-␤ activity. Currently, sarpogrelate hydrochloride, a potent 5-HT 2A receptor antagonist that inhibits 5-HTinduced vasoconstriction and platelet aggregation (16), is used clinically as antiplatelet drugs for prevention of thrombosis in atherosclerotic disease. Takahashi et al (17) reported that sarpogrelate hydrochloride reduced the degree of UAE, indicating the potential usefulness of this agent for the protection of development and progression of diabetic nephropathy.…”

Section: -Correlation Between Log (Plasma 5-hiaa) Concentration and Pmentioning

confidence: 99%

Association Between Urinary Albumin Excretion and Plasma 5-Hydroxyindole-3-Acetic Acid Concentration in Men With Type 2 Diabetes

et al. 2007

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Serotonin (5-hydroxytryptamine [5-HT]) mediates vasoconstriction and induces the activation of platelets, which may promote atherosclerosis. Plasma 5-HT concentrations have been reported to be high in diabetic patients (1,2); this may be one of the underlying mechanisms of diabetes complications. The 5-HT 2A receptor has been identified in glomerular mesangial cells (3), suggesting involvement of 5-HT in the development of diabetic nephropathy through proliferation and matrix sysnthesis in mesangial lesions. Male sex is an independent risk factor for cardiovascular disease (4). Moreover, elevated urinary albumin excretion (UAE) has been reported to be associated with increased risk of cardiovascular mortality (5). Few studies have examined the association between plasma 5-HT concentration and atherosclerosis (6). To our knowledge, a relationship between plasma 5-HT concentration and degree of UAE has never been explored in men with type 2 diabetes. In this study, we evaluated the relationships between plasma 5-hydroxyindole-3-acetic acid (5-HIAA), a derivative end product of 5-HT, concentration and degree of UAE, and markers of subclinical atherosclerosis, such as pulse wave velocity (PWV), anklebrachial index (ABI), carotid intimamedia thickness (IMT), or plaque score in men with type 2 diabetes.RESEARCH DESIGN AND METHODS -The relationships of plasma 5-HIAA concentrations with degree of UAE and major cardiovascular risk factors were investigated in 205 consecutive men with type 2 diabetes recruited from the outpatient clinic at the Kyoto Prefectural University of Medicine (Kyoto, Japan). Additionally, the relationships between plasma 5-HIAA concentration and PWV or ABI (n ϭ 160) and between plasma 5-HIAA concentration and IMT or plaque score (n ϭ 102) were investigated in a subgroup of patients.Plasma 5-HIAA concentrations (normal range 1.8 -6.1 ng/ml) were measured by high-performance liquid chromatography. The intra-assay coefficients of variation (CVs) were 2.1, 2.0, and 0.9% for plasma 5-HIAA concentrations of 25.27, 41.30, and 95.09 ng/ml, respectively, and the interassay CVs were 3.9, 3.3, and 2.4% for plasma 5-HIAA concentrations of 7.45, 20.55, and 60.83 ng/ml, respectively. UAE was measured with an immunoturbidimetric assay. A mean value for UAE was determined from three urine collections. Patients were excluded if they were taking any medications that might affect plasma 5-HIAA concentrations (e.g., 5-HT receptor blockers). Approval for the study was obtained from the local research ethics committee, and informed consent was obtained from all participants. Brachial-ankle PWV and ABI were measured using a Colin Waveform Analyzer (form PWV/ABI; Colin Medical Technology, Komaki, Japan) (7). B-mode ultrasonographic imaging of the carotid artery was performed as previously described (8). Because plasma 5-HIAA concentration and UAE showed skewed distributions, log transformation of these values was carried out before performing correlation and regression analysis. The relationships between log (plasma 5-HI...

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Section: -Correlation Between Log (Plasma 5-hiaa) Concentration and Pmentioning

confidence: 99%

Association Between Urinary Albumin Excretion and Plasma 5-Hydroxyindole-3-Acetic Acid Concentration in Men With Type 2 Diabetes

et al. 2007

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“…Sarpogrelate, which is a 5-HT 2 antagonist and was introduced as a therapeutic agent for treatment of isch- Gong/Nakamura/Hattori/Ohnuki/Rashid/ Nakazawa/Watanabe/Nagatomo emic diseases associated with thrombosis [8], has been demonstrated to be selective and to show high affinity for the 5-HT 2A subtype, lacking significant 5-HT 1 , 5-HT 3 , ß-adrenoceptor, histamine H 1 , H 2 and muscarinic M 3 antagonistic activity [9][10][11]. However, there have been no reports of the inhibitory effects of sarpogrelate on the contraction-relaxation of coronary arteries.…”

Section: Introductionmentioning

confidence: 99%

A Novel 5-HT<sub>2</sub> Antagonist, Sarpogrelate Hydrochloride, Shows Inhibitory Effects on Both Contraction and Relaxation Mediated by 5-HT Receptor Subtypes in Porcine Coronary Arteries

Gong¹,

Nakamura²,

Hattori³

et al. 2000

Pharmacology

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In isolated porcine coronary arteries, concentrations of 5-HT (10^–8 to 3 × 10^–5 mol/l), α-methylserotonin (α-Me-5-HT, 10^–8 to 3 × 10^–5 mol/l) and ergonovine (10^–9 to 3 × 10^–4 mol/l) produced contraction, whereas high concentrations (10^–5 to 10^–4 mol/l) of these drugs produced relaxation. Both sarpogrelate and ketanserin produced rightward shifts of contraction concentration-response curves induced by 5-HT and α-Me-5-HT at the concentration from 10^–9 to 3 × 10^–5 mol/l, and only sarpogrelate inhibited the relaxation at high concentrations of 5-HT and displayed 155% of maximal contraction at 10^–4 mol/l 5-HT. On the other hand, sarpogrelate and ketanserin did not show any inhibitory effects on the relaxation induced by high concentrations of ergonovine. These results suggested that sarpogrelate and ketanserin show different inhibitory effects on the relaxation induced by high concentrations of 5-HT, indicating that these two drugs may have different affinities to 5-HT receptor subtypes that may be involved in relaxation.

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“…The change in ∆F was measured in patients with autoimmune Raynaud's phenomenon, SSc or MCTD after administering the serotonin (5-hydroxytryptamine) receptor antagonist salpogrelate 16 at a dose of 300 mg/day for 4 weeks. Measurements were taken in the same way as described in the section on measuring skin hardness before and after salpogrelate therapy.…”

Section: Measurement Of Treatment Efficacymentioning

confidence: 99%

A New Tactile Skin Sensor for Measuring Skin Hardness in Patients with Systemic Sclerosis and Autoimmune Raynaud's Phenomenon

et al. 2004

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We used a new tactile sensor to measure the elastic properties of skin in patients with systemic sclerosis or Raynaud's phenomenon. The sensor consists of a piezoelectric vibrator with vibration pickup to measure frequency changes when the sensor is placed on the skin. The mean frequency change at the skin surface of the proximal third phalanx in patients with systemic sclerosis was significantly lower than in age-and sexmatched controls. The results in systemic sclerosis patients were statistically correlated to the Modified Rodnan Skin Thickness Score. This technique was also used to measure the therapeutic efficacy of salpogrelate, a new specific serotonin receptor antagonist. A greater mean frequency change was seen after treatment. We conclude that this new tactile sensor is useful for quantitatively measuring skin sclerosis and may help determine the efficacy of therapeutic treatments.

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Syntheses and platelet aggregation inhibitory and antithrombotic properties of [2-[(.omega.-Aminoalkoxy)phenyl]benzenes

Cited by 51 publications

References 0 publications

Association Between Urinary Albumin Excretion and Plasma 5-Hydroxyindole-3-Acetic Acid Concentration in Men With Type 2 Diabetes

Association Between Urinary Albumin Excretion and Plasma 5-Hydroxyindole-3-Acetic Acid Concentration in Men With Type 2 Diabetes

A Novel 5-HT<sub>2</sub> Antagonist, Sarpogrelate Hydrochloride, Shows Inhibitory Effects on Both Contraction and Relaxation Mediated by 5-HT Receptor Subtypes in Porcine Coronary Arteries

A New Tactile Skin Sensor for Measuring Skin Hardness in Patients with Systemic Sclerosis and Autoimmune Raynaud's Phenomenon

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