Effect of synthetic motilin and related polypeptides on contraction of gastrointestinal smooth muscle

Segawa, Tomio; Nakano, Masahiro; Kai, Yoshiaki; Kawatani, Hiroki; Yajima, Haruaki

doi:10.1111/j.2042-7158.1976.tb02822.x

Cited by 35 publications

(9 citation statements)

References 10 publications

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“…It is known that in dog, motilin increases the motility of the stomach and small intestine by stimulating the cholinergic neurons, [3][4][5] whereas in rabbit and human it produces the contractions of the stomach, pylorus and duodenum by direct action on the smooth muscle cells. [6][7][8][9][10][11] The mechanisms of the increase in gastrointestinal (GI) motility differ with the animal species.…”

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confidence: 99%

Effects of SK-896, a New Human Motilin Analogue ([Leu13]motilin-Hse), on Postoperative Ileus in Dogs after Laparotomy.

Furuta

Takeda

Nakayama

et al. 2002

Biological & Pharmaceutical Bulletin

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The effects of SK-896, a new human motilin analogue ([Leu 13 ]motilin-Hse), on digestive tract motility in postoperative ileus were evaluated in a dog model of ileus after laparotomy. SK-896 was intravenously administered at 0.17, 0.33 and 0.67 m mg/kg starting soon after operation and then at 6-h intervals, for a total of 9 times. SK-896 progressively, dose-dependently and significantly increased the duodenal motility from 1 h after operation. The recovery time of the gastrointestinal-interdigestive migrating complex (GI-IMC) activity, which is an indicator of normal gastrointestinal tract activity after laparotomy, was 56.5؎5.0 h in the control group. SK-896 significantly shortened this recovery time. On the other hand, the plasma SK-896 concentrations declined diexponentially after administration, and can be described by a linear pharmacokinetic model within the dose range used. In addition, the pharmacokinetics of SK-896 did not change significantly at any postoperative time. There was no correlation between the plasma SK-896 concentrations and the intensity of duodenal motility, because the activity in the duodenum decreased transiently 13 h after laparotomy and increased with time thereafter. The changes in the activity are considered to reflect the progressive changes in the state of ileus. In conclusion, SK-896 increased the duodenal motility significantly, shortening the recovery time of GI-IMC-like activity in dogs with post-laparotomy ileus. Therefore, it is expected from these results that SK-896 would be useful and effective for the treatment of gastroparalysis after abdominal surgery.

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mentioning

confidence: 99%

Effects of SK-896, a New Human Motilin Analogue ([Leu13]motilin-Hse), on Postoperative Ileus in Dogs after Laparotomy.

Furuta

Takeda

Nakayama

et al. 2002

Biological & Pharmaceutical Bulletin

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“…The APEX-3D expert system was used to identify biophoric structural patterns that are common to 18 A and derivatives 1-17) showing different levels of gastrointestinal motor stimulating activity. The training set molecules are schematically presented in Figure 1.…”

Section: Training Set Results and External Test Set Predictionsmentioning

confidence: 99%

“…Fragments 1-10 and 1-11 induced significant contractile activity but shorter fragments were inactive (21,23). C-terminal fragments failed to stimulate any contractile activity (18,20). The N-terminal phenylalanine residue (Phe') appears to be very important for activity because its substitution or deletion provoked an important loss of activity (21,23).…”

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confidence: 99%

Identification of the motilide pharmacophores using quantitative structure activity relationships

Khiat

Boulanger

1998

The Journal of Peptide Research

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To cite this article: Khiat, A. d Boulanger, Y . (1998) Identification of the motilide pharmacophores using quantitative structure activity relationships. 1. Peptide Res. 52, 321-328. Abstract: Erythromycin A and some derivatives have been shown to act as agonists at the motilin receptor site (motilides) and a structural similarity between these molecules and the N-terminal fragment of motilin has been proposed. Conformational analysis and three-dimensional quantitative structure-activity relationship (3D-QSAR) methods have been used t o determine the homology between a series of erythromycin A derivatives and motilin 1-10, A total of 18 compounds has been studied to correlate the gastrointestinal motor stimulating (GMS) activity with the structure-related parameters determined by 3D-QSAR. Two models with good predictive power of the GMS activity are presented, leading to the prediction of motilin 1-10 activity. The models are consistent with the majority of the data available. The most significant parameters for GMS activity are a favorable dispersion interaction from the quaternary ammonium group of the desosamine ring. In motilin 1-10, the aromatic side chains of Phe' and Tyr7 seem to play the same role as the quaternary ammonium group in models 1 and 2, respectively. Some hydroxyl groups of erythromycin A derivatives and hydrophobic groups of the Val2 and He4 side chains of motilin also contribute to the GMS activity. The experimental GMS activities measured are in good agreement with the predicted values, with correlation coefficient values of 0.98 and 0.94 in models 1 and 2, respectively. Abbreviations: 3D-QSAR, three-dimensional quantitative structure-activity relationships; EM-A, erythromycin A; GMS, gastrointestinal motor stimulating; NOESY, nuclear Overhauser enhancement spectroscopy; RMSA, root mean square error based on all compounds with degrees of freedom correction; RMSP, root mean square error based on "leave-one-out" with no degrees of freedom correction; SAR, structure-activity relationships.

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“…In addition, it has been reported that motilin receptors exist in the human gastrointestinal tract smooth muscle tissue [13]. However, motilin was reported to have no effect on preparations isolated from canine gastrointestinal tract in vitro [14]. Moreover, 125 I-motilin did not bind to homogenate preparations from canine stomach tissue [13].…”

Section: Introductionmentioning

confidence: 97%

Gastroprokinetic Effect and Mechanism of SK-896, a New Motilin Analogue, during the Interdigestive Period in Conscious Dogs

Tsukamoto

Tagi²,

Nakazawa³

et al. 2001

Pharmacology

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SK-896 [(Leu¹³)motilin-Hse] is a new human motilin analogue synthesized from Escherichia coli using a biotechnological method. We investigated the gastrointestinal motor-stimulating effect of SK-896 and the mechanism of this effect using implanted force transducers in conscious dogs. Infusion of SK-896 during phase I in the interdigestive state induced interdigestive migrating contractions like motility in the gastroduodenum. The motility index (MI_0–20) of gastric antrum motor activity induced by SK-896 was increased dose dependently (r = 0.830, p < 0.001), and the MI_0–20 induced by SK-896 at a dose of 0.25 µg/kg/h for 20 min was the same as that for spontaneous phase III contractions. The SK-896-induced MI_0–20 was significantly decreased by atropine, hexamethonium, dopamine, granisetron, and yohimbine. Conversely, ketanserin, phentolamine, timolol, and naloxone did not have significant effects on SK-896-induced MI_0–20. The effects of these drugs on human motilin (0.25 µg/ kg/h for 20 min) induced MI_0–20 were the same as those of SK-896. These results indicate that SK-896 induces gastrointestinal motility during the interdigestive period in dogs with regulation of acetylcholine release from the cholinergic nerve terminal via the parasympathetic nervous system in the same fashion as human motilin.

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Effect of synthetic motilin and related polypeptides on contraction of gastrointestinal smooth muscle

Cited by 35 publications

References 10 publications

Effects of SK-896, a New Human Motilin Analogue ([Leu13]motilin-Hse), on Postoperative Ileus in Dogs after Laparotomy.

Effects of SK-896, a New Human Motilin Analogue ([Leu13]motilin-Hse), on Postoperative Ileus in Dogs after Laparotomy.

Identification of the motilide pharmacophores using quantitative structure activity relationships

Gastroprokinetic Effect and Mechanism of SK-896, a New Motilin Analogue, during the Interdigestive Period in Conscious Dogs

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