Pharmacological Analysis of Receptors Involved in the Late, Tachykininergic Contractile Response to Electrical Transmural Stimulation in Isolated Rabbit Iris Sphincter Muscle

Yamaguchi, Taichi; Aihara, Kazuyuki; Yamada, Shin‐ichi; Narita, Sen-ichi; Kogi, Kentaro

doi:10.1254/jjp.62.363

Cited by 6 publications

(2 citation statements)

References 40 publications

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“…It is well known that antisecretory drugs such as H 2 and/or muscarinic antagonist and proton pump inhibitors blocked the ulcerative lesions in the Shay model (22). We carried out a series of functional studies in which we analysed the response to different agonists using isolated preparations.…”

Section: Discussionmentioning

confidence: 99%

Antiulcerogenic Mechanisms of Dehydrocrotonin, a Diterpene Lactone Obtained from Croton cajucara

et al. 1999

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The bark of Croton cajucara Benth, is used in Brazilian folk medicine as an infusion to treat gastrointestinal disorders. The aim of the present study was to assess the mechanisms involved in the antiulcerogenic activity of dehydrocrotonin (DHC), a diterpene isolated from C. cajucara bark. We studied the effects of DHC on pylorus ligature (Shay) in mice treated with the drug (100 mg/kg) by the intraduodenal route. DHC did not induce any alteration in gastric volume in Shay mice but modified the pH and total acid concentration of gastric juice. Incubation of gastric juice with DHC did not reduce gastric acidity compared to control. We also investigated the effects of DHC on the response to histamine of right atria isolated from guinea pigs and on the response to carbachol of stomach fundus strips from rats. The concentration-response curves for the chronotropic effect of histamine in guinea pig right atria were shifted to the right, with a significant decrease in the maximum response, in the presence of DHC. Similar results were obtained with DHC (30 microM) for the concentration-response curves to carbachol in the isolated rat stomach. The ability of DHC to increase PGE2 release from rat stomach mucous cells was also studied. We observed that DHC induced a significant increase in PGE2 production (60% compared to control). In addition, the effects of DHC on the healing of acetic acid-induced gastric ulcer in rats were evaluated 14 days after acid injection. Oral administration of DHC (100 mg/kg per day) for 14 consecutive days had no effect on gastric ulcer healing in rats. Thus, the protective effect of DHC on induced gastric lesions could be due to synergistic effects, e.g., an increase in PGE2 release and non-competitive antagonism of H2-receptors and of muscarinic receptors. Whereas the former result represents an increase in the protective factors, the latter one shows a decrease in the aggressive factors against the gastric mucosa.

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Section: Discussionmentioning

confidence: 99%

Antiulcerogenic Mechanisms of Dehydrocrotonin, a Diterpene Lactone Obtained from Croton cajucara

et al. 1999

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“…These drugs have a common precursor, 7-methyl-2-naphthalenecarbonitrile (1), and several methods have been reported for preparation of this compound. [6][7][8][9][10] Earlier syntheses of compound 1 are multi-step procedures 6,8) or require high temperature (flame-heating or heating to 400°C), 7,9) and hence they are impractical and unsuitable for commercial exploitation. More recently, Yokoyama et al have described the preparation of compound 1 in four steps, in which 2,7-dimethylnaphthalene was used as the starting material.…”

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confidence: 99%

An Easy Access to 7-Methyl-2-naphthalenecarbonitrile

Koshio¹,

Ishihara²,

Yamada³

et al. 2005

CHEMICAL & PHARMACEUTICAL BULLETIN

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Thromboembolic diseases continue to be a leading cause of morbidity and mortality in the developed world, and the use of anticoagulant drugs is a primary clinical strategy to treat and prevent these diseases. Factor Xa inhibitors have the potential to be superior anticoagulant agents, and thus the search for novel factor Xa inhibitors has emerged as one of the most active areas of current drug discovery.Several potent factor Xa inhibitors containing naphthylamidine moieties have been reported, [1][2][3][4][5] and representative structures of these inhibitors are shown in Fig. 1. These drugs have a common precursor, 7-methyl-2-naphthalenecarbonitrile (1), and several methods have been reported for preparation of this compound.6-10) Earlier syntheses of compound 1 are multi-step procedures 6,8) or require high temperature (flame-heating or heating to 400°C), 7,9) and hence they are impractical and unsuitable for commercial exploitation. More recently, Yokoyama et al. have described the preparation of compound 1 in four steps, in which 2,7-dimethylnaphthalene was used as the starting material. 10) However, 2,7-dimethylnaphthalene is not readily available from commercial sources, and this method also involves a selective transformation of a symmetrical starting material to an asymmetrical target compound. These two problems contribute to decreased synthetic efficacy. Due to the high worldwide market value of factor Xa inhibitors, development of an effective synthetic procedure for the synthesis of the key precursor 1 remains as an important and challenging task. Herein, we present a practical and efficient synthesis of 7-methyl-2-naphthalenecarbonitrile (1) starting from two common, readily available starting materials: m-tolualdehyde (2) and 3-cyanopropionaldehyde dimethyl acetal (3).Teague et al. have reported that condensation of a 3-cyanopropionaldehyde dialkyl acetal with a methoxy-activated aromatic aldehyde, followed by treatment with sulfuric acid, yields a substituted naphthalene product.11) Although this method is limited to activated benzaldehydes such as methoxybenzaldehyde, we adapted it for our target compound using a weakly activated benzaldehyde, m-tolualdehyde (Chart 1). Condensation of 2 with 3 in the presence of LDA (lithium diisopropylamide) gave intermediate alcohol 4, and the crude alcohol was then refluxed in 20% aqueous sulfuric acid to afford compound 1 in 43% yield after chromatographic purification (Chart 1, Entry 1). The more hindered cyclization product, 5-methyl-2-naphthalenecarbonitrile, was not observed.Several different reaction conditions were used in optimizing the reaction for multi-gram preparations, and the results are summarized in Chart 1. Sodium amide, 12) n-butyllithium, 13-15) a combination of di-n-butylboryl triflate and diisopropylamine, 16) potassium t-butoxide, 17) and a combination of proazaphosphatrane and magnesium sulfate 18) have been used as condensation reagents for acetonitrile with benzaldehyde. Our attention was drawn to the reaction in the presence of potassi...

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Pharmacokinetic Properties of a Novel Gastric Proton Pump Inhibitor, (±)-2-[(4-Methoxy-6,7,8,9-Tetrahydro-5h-Cyclohepta[d]Pyridin-9-yl) Sulfinyl]-1h-Benzimidazole Sodium Salt, in Healthy Subjects

Uematsu¹,

Nakano

Kosuge

et al. 1994

Journal of Pharmaceutical Sciences

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Pharmacological Analysis of Receptors Involved in the Late, Tachykininergic Contractile Response to Electrical Transmural Stimulation in Isolated Rabbit Iris Sphincter Muscle

Cited by 6 publications

References 40 publications

Antiulcerogenic Mechanisms of Dehydrocrotonin, a Diterpene Lactone Obtained from Croton cajucara

Antiulcerogenic Mechanisms of Dehydrocrotonin, a Diterpene Lactone Obtained from Croton cajucara

An Easy Access to 7-Methyl-2-naphthalenecarbonitrile

Pharmacokinetic Properties of a Novel Gastric Proton Pump Inhibitor, (±)-2-[(4-Methoxy-6,7,8,9-Tetrahydro-5h-Cyclohepta[d]Pyridin-9-yl) Sulfinyl]-1h-Benzimidazole Sodium Salt, in Healthy Subjects

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