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PubMed1995

Increases in plasma motilin follow each episode of gallbladder emptying during the interdigestive period, and changes in serum bile acid concentration correlate to plasma motilin.

BACKGROUND: The relationship between each single period of gallbladder emptying during the migrating motor complex (MMC) cycle and changes in concentration of plasma motilin and serum bile acids is unknown. METHODS: The variations in the concentration of plasma motilin and serum bile acids in relation to interdigestive gallbladder motility and the MMCs was studied in nine healthy male volunteers. A method combining biliary scintigraphy (99mTc-labelled dimethyl-iminodiacetic acid) and continuous pressure recording from the antroduodenal region was used. RESULTS: During 9 MMC cycles a total of 15 episodes of gallbladder emptying were observed with a median (range) duration of 25 min (15-45 min). Each episode of gallbladder emptying was followed by a steep increase in plasma motilin, reaching a median value of 30 pmol/l (13-43 pmol/l), corresponding to an increase of 18 pmol/l (4-33 pmol/l). The increase in plasma motilin started at the beginning of gallbladder emptying, but the peak value was not reached until a median of 20 min (10-45 min) later. Low plasma motilin concentrations were found between the emptying periods in cases with two or more emptying during the MMC cycle. The serum concentration of bile acids also showed a cyclic variation in relation to gallbladder motility. During periods of gallbladder emptying serum bile acid concentration had a median value of 1.78 mumol/l, as compared with a median value of 1.17 mumol/l during periods of gallbladder filling. This difference did not reach significance, however. In the pooled data from all subjects, a significant correlation (p < 0.01) between the serum concentration of bile acids and plasma concentration of motilin was found. CONCLUSION: Gallbladder emptying was followed by a steep increase in plasma motilin concentration, and in cases of two or more emptying periods during the MMC cycle the concentration decreased in between. The shape of the serum bile acid profile is dependent on the intestinal transport and absorption of bile acids, and the significance of the cyclic variation in serum concentration of bile acids in relation to plasma motilin, gallbladder motility, and MMC needs further investigation.

Adult↗
PubMed1976

Motilin and motilin analogues: mode of action.

Natural porcine motilin (13-methionine-motilin) and its synthetic position 13-substituted analogues, 13-norleucine-motilin and 13-leucine-motilin, are of equal efficacy for gastrointestinal motor activity. Pharmacological in vitro analysis reveals that motilin effects on the gastrointestinal muscle are not mediated via nervous pathways but are brought about by direct action of the polypeptide on the muscle cell. As the contractile response to motilin can be abolished by the Ca++ antagonistic compound verapamil, a role for motilin in the transport of Ca++ to the cytosol of intestinal smooth muscle might be considered. Ca++ fluxes seem to be linked to intracellular cyclic guanosine-3':5'-monophosphate and the antagonistic cyclic adenosine-3':5'-monophosphate. By contrast, in motilin-stimulated gastric pepsin secretion, there is no evidence for a mediating role of cyclic nucleotides. It is more likely that the pepsigogic effect is brought about by augmented gastric mucosal blood flow.

Animals↗
PubMed1988

Erythromycin and its derivatives with motilin-like biological activities inhibit the specific binding of 125I-motilin to duodenal muscle.

Erythromycin, one of the macrolide antibiotics, and its derivatives had been found to mimic actions of exogenous motilin, a gastrointestinal peptide hormone. We found that some of the macrolide compounds inhibited the specific binding of 125I-motilin to rabbit duodenum muscle at 15 C in a dose-dependent fashion. The inhibitory activity of several macrolides examined did not relate to their antibacterial activity but to their motilin-like activity. A 50% inhibition by EM536, a non-antibacterial erythromycin derivative with the highest motilin-like activity, was obtained at 3-40 nM and little higher than that of non-radioactive motilin (5-6 nM) under the present conditions. The results suggest that erythromycin and its derivatives mimic physiological actions of motilin by acting as agonists for a motilin receptor.

Animals↗
PubMed1990

Development of motilin receptors and of motilin- and erythromycin-induced contractility in rabbits.

The development of the motilin receptor was studied through contraction and binding studies of groups of three rabbits aged between 2 and 289 days. The contractility of small intestinal smooth muscle strips was measured isotonically. The aborally decreasing gradient in response to motilin, known to exist in adult rabbits, was already present at day 8 (maximum contractile responses expressed as a percent of the maximal response to acetylcholine were 77% +/- 9%, 34% +/- 10%, and 25% +/- 8% for duodenal, jejunal, and ileal strips, respectively). Throughout the observation period, the doses of motilin and its agonist erythromycin that were required to induce 50% of the response remained constant and were not significantly different from doses required for adults (their negative logarithms were 8.55 +/- 0.35 and 5.70 +/- 0.25, respectively). The correlation between the maximum contractile response toward motilin and erythromycin was almost perfect (r2 = 0.82). Binding studies with iodinated norleucine13-porcine motilin were performed using antral smooth muscle tissue homogenates. The maximum number of binding sites increased rapidly after 8 days (3.3 +/- 0.4 fmol/mg protein) and reached a peak at 21 days (20.7 +/- 1.4 fmol/mg protein), but decreased at that point toward the adult value (40 days, 10.6 +/- 1.3; 289 days, 9.8 +/- 1.1 fmol/mg protein). The dissociation constant, however, remained unchanged. The peak value of receptor density occurred at about the time that the rate of increase of the length of the intestine and of the weight of the antrum were at maximum levels (at 18 and 27 days, respectively). Motilin receptors are expressed early postnatally, and the regional gradient in sensitivity towards motilin is also established soon after birth. If applicable to humans, an early response to erythromycin may have therapeutic value.

Acetylcholine↗
PubMed1994

Studies on the structure-activity of motilin in vivo. Effect of motilin synthetic analogues in conscious dog.

Synthetic analogues of motilin were tested for their capacity to stimulate the intestinal motor activity of the conscious dog. Physiological doses (75 pmol/kg) of motilin 1-22 and of motilin fragments 1-21, 1-20 and 1-19 induced premature periods of phase III activity in all tested animals. Motilin fragments 1-15, 1-12, 1-11 and 1-10 failed to influence the intestinal myoelectrical activity even when given at doses 10-times superior (750 pmol/kg). Motilin-like-immunoreactivity was measured in plasma during the analogues infusion. During the infusion of the bioactive analogues (1-22, 1-21, 1-20, 1-19), plasma motilin increased by 174 +/- 25 fmol/ml while a small rise (22 +/- 7.6 fmol) was noted with the inactive fragments (P < 0.001). Our data are in agreement with the in vitro findings that the N-terminal portion of the motilin molecule is responsible for its biological activity and suggests that the middle portion of the molecule is important to prevent degradation and maintain biological activity in vivo.

Animals↗
PubMed2002

The motilin pharmacophore in CHO cells expressing the human motilin receptor.

We performed a structure-activity study with the human motilin receptor, which was recently cloned from thyroid tissue. N-terminal fragments, Ala-analogs of motilin, and motilides were tested in a cell line that expresses the cloned human motilin receptor and apoaequorin. Full potency to induce calcium fluxes was obtained with N-terminal fragments of 14 amino acids. Motilin fragments 1-14 in which residues 1 (Phe), 4 (Ile), and 7 (Tyr) were replaced by Ala showed the largest reduction in potency. Only motilides with an enol configuration had markedly higher potencies compared to erythromycin A. The potencies to induce Ca(2+) fluxes correlated strongly with rabbit binding and contractility data, suggesting that the cloned receptor is indeed the motilin receptor, responsible for contractile effects. Conservation of the motilin pharmacophore in evolution indicates an important physiological role of motilin.

Aequorin↗
PubMed1998

Isolation and sequence of cDNA encoding the motilin precursor from monkey intestine. Demonstration of the motilin precursor in the monkey brain.

The motilin precursor cDNA has been isolated and sequenced from a cDNA library prepared from monkey small intestine. The sequence indicates a 345 bp open reading frame, a 63 bp 5' untranslated region and a 154 bp 3' untranslated region. The sequence encodes a 115 amino acid motilin precursor composed of a 25 amino acid signal peptide, the 22 amino acid motilin peptide and a 68 amino acid motilin associated peptide (MAP). Compared with the human motilin precursor cDNA, there are two amino acid substitutions in the signal peptide, one in motilin and four in the MAP. The presence of the motilin precursor in hypothalamus, hippocampus and cerebellum was demonstrated by RT-PCR.

Amino Acid Sequence↗
PubMed1981

Motilin-antimotilin reaction reveals two antigenic determinants in motilin.

The reaction of motilin with four rabbit antimotilin sera raised by immunization with synthetic porcine motilin-bovine serum albumin conjugate was studied with respect to various binding parameters and specificity. All four antisera exhibited an extremely high degree of specificity and high affinity (K greater than 10(11) M-1) for porcine motilin. Studying the various synthetic motilin fragments. These antisera appeared to contain binding sites reacting strongly with the N-terminal sequence in which the first three amino acid residues are essential for high affinity binding. One of the antisera, R-3-6, appeared to contain approximately 20% of its binding sites with high affinity for C-terminus-containing fragments. These results suggest that motilin possesses two antigenic domains along its primary structure; one contains the N-terminal tripeptide and the other contains the C-terminal nanopeptide as essential parts. Thus, in addition to heterogeneity in affinity, a given antibody preparation may be heterogenous with respect to the specificity along the sequence of a peptide. Gel filtration studies of the methanol extracts of human and dog plasma indicated that an immunoreactive motilin-like material with a molecular size similar to natural porcine motilin was measured by our routine radioimmunoassay.

Animals↗
PubMed2005

Demonstration of a specific site of covalent labeling of the human motilin receptor using a biologically active photolabile motilin analog.

The motilin receptor belongs to a group of class I G protein-coupled receptors that also includes the growth hormone secretagogue and ghrelin receptors. These represent clinically useful targets for pharmacotherapy. Their potentially unique structures and the molecular basis of their binding are not yet clear. We previously reported the initial affinity labeling of a region within this receptor (a cyanogen bromide fragment extending from the first to the second extracellular loop) using a position 1 photolabile motilin analog. To extend our understanding of the molecular basis of motilin binding, we have developed an additional radioiodinatable motilin analog probe having site of covalent attachment in position 5. This was a full agonist that bound to the motilin receptor specifically and with high affinity, and that efficiently established a single covalent bond to its receptor. Sequential chemical and enzymatic cleavage of labeled wild-type and mutant motilin receptor constructs established that the region of labeling was within the third extracellular loop. This was further localized to Phe(332) using radiochemical Edman degradation sequencing. These data provide the first spatial approximation constraint that can be used in the docking of this peptide ligand to its receptor. We hope that a series of such constraints can be determined to provide adequate structural information to begin to elucidate the conformation of this agonist-bound receptor and to ultimately be useful in the rational design of drugs acting at this important target.

Amino Acid Sequence↗
PubMed1986

Evidence of somatostatin as a humoral modulator of motilin release in man. A study of plasma motilin and somatostatin during intravenous infusion of somatostatin, secretin, cholecystokinin, and gastric inhibitory polypeptide.

In six healthy persons receiving graded intravenous infusions of synthetic somatostatin the plasma motilin concentrations decreased significantly (p less than 0.05) already with doses giving physiological plasma somatostatin levels, and a rebound of plasma motilin was observed after cessation of infusion of pharmacological somatostatin doses. After an intravenous secretin infusion (280 pmol/kg-h) producing pharmacological plasma secretin concentrations, a comparable plasma somatostatin increase was observed together with a substantial decrease in plasma motilin (p less than 0.05). Infusion of cholecystokinin in a pharmacological dose and of gastric inhibitory polypeptide (GIP) in doses giving plasma GIP levels in the physiological range had no effect on plasma somatostatin or motilin. Circulating plasma somatostatin may be a physiological modulator of the motilin release, and the plasma motilin fall seen during infusion of pharmacological doses of secretin may possibly be explained by the secretin-induced somatostatin release occurring simultaneously.

Adult↗
PubMed1976

Gastroduodenal motor response to natural motilin and synthetic position 13-substituted motilin analogues: a comparative in vitro study.

Motor effects of graded concentrations of pure natural porcine motilin (13-Met-M) and synthetic motilin analogues - the methionine in position 13 substituted with either norleucine (13-Nle-M) or leucine (13-Leu-M) - on the rabbit, guinea-pig, rat, and human gastrointestinal smooth muscle were examined in vitro. Congruent species specificity of the motor activity of the motilins under study could be demonstrated in that muscle strips from rabbit and man were highly sensitive, whereas guinea-pig and rat preparations proved refractory to the polypeptides. In rabbit duodenal muscle and fundic muscle of the human stomach, graded concentrations of 13-Met-M, 13-Nle-M, and 13-Leu-M, respectively, produced graded increases in the contractile responses. The concentration-response curves were superimposable. Calculated maximal contractile responses (CMR's) and polypeptide doses for one-half maximal responses (D50 values) were not significantly different between the three motilins. Moreover, pharmacological analysis revealed that the motor effects of 13-Met-M, 13-Nle-M, and 13-Leu-M are uniformly not mediated via nervous pathways: neither blockage of axonal conduction by tetrodotoxin nor anticholinergic action by atropine exerted any detectable influence. Viewing the data presented, one may conclude that in man and rabbit, 1) natural porcine motilin and its synthetic position 13-substituted analogues, 13-Nle-M and 13-Leu-M, are of equal efficacy for gastroduodenal motor activity, and 2) position 13 of the amino acid sequence of motilin (22-residue chain) is not pertinent to the active site of the molecule.

Acetylcholine↗
PubMed1995

Purification and amino acid sequence of human motilin isolated from a motilin containing liver metastasis.

The acid extract of a liver metastasis from a patient with elevated plasma motilin levels contained large quantities of motilin (3.37 micrograms/ml). The extract was concentrated on a C18-column and motilin was isolated by gel chromatography (Sephadex G-50) followed by cation ion exchange chromatography (HR5/5 Mono-S) and three successive steps of reverse phase chromatography (Nucleosil 300-5 C18). The pure peptide was sequenced and the identity of porcine and human motilin was confirmed. This is the first report of a tumor containing large amounts of motilin.

Amino Acid Sequence↗
PubMed2001

Design and synthesis of N-terminal cyclic motilin partial peptides: a novel pure motilin antagonist.

Motilin antagonist was designed and synthesized on the basis of the structure-activity relationship analysis of porcine motilin that we reported recently. The drug design was performed on a specific concept to reduce a flexibility of peptide conformation of porcine motilin partial peptide by its cyclization. The cyclic peptide was synthesized using Boc (tert-butyloxycarbonyl) solid phase methodology, followed by cyclization using the azide procedure, and tested for the binding activity to motilin receptor and smooth muscle contractile activity. The cyclic peptides 3, 4, and 5 showed antagonistic property on contraction assay (pA2 [the negative logarithm of molar concentration of antagonist causing a 2-hold shift to the right of the concentration-response curve for motilin]: 4.5, 4.34, and 4.04, respectively, in rabbit duodenum) and no contractile activity even at high concentration.

Amino Acid Sequence↗
PubMed2002

Design and synthesis of motilin antagonists derived from the [1-4] fragment of porcine motilin.

A series of cyclic peptides having the general structure H-Phe-c[-N(epsilon)-Lys-X-NH-(CH(2))(n)-CO-] were designed on the basis of structure-activity relationship studies of motilin. All were motilin antagonists. The cyclic peptides, in which X is a 3-tert-butyl-substituted tyrosine residue (H-Phe-c[-N(epsilon)-Lys-Tyr(3-tBu)-beta Ala-] (3), H-Phe-c[-N(epsilon)-Lys-Tyr(3-tBu)-Gly-] (6), H-Phe-c[-N(epsilon)-Lys-Tyr(3-tBu)-Abu-] (7), and H-Phe-c[-N(epsilon)-Lys-Tyr(3-tBu)-Ahx-] (8)) showed potent motilin receptor antagonistic activity in the rabbit smooth muscle (pA(2) > 7). The 3-tert-butyl Tyr was found to be the moiety responsible for enhanced binding to the motilin receptor, while the size of the ring had little importance.

Animals↗
PubMed1985

The regional distribution and the chemical, chromatographic, and immunologic characterization of motilin brain peptides: the evidence for a difference between brain and intestinal motilin-immunoreactive peptides.

Motilin-like immunoreactive peptides (MLIPs) have been detected in the brain by radioimmunoassay (RIA), (Yanaihara, C., H. Sato, N. Yanaihara, S. Naruse, W. G. Forssman, V. Helmstaedter, T. Fujita, K. Yamaguchi, and K. Abe (1977) Adv. Exp. Biol. Med. 106: 269-283; Chey, W. Y., R. Escoffery, F. Roth, T. M. Chang, and H. Yajima (1980) Regul. Pept. Suppl. 1: 519; O'Donohue, T. L., M. C. Beinfeld, W. Y. Chey, T. M. Chang, G. Nilaver, E. A. Zimmerman, H. Yajima, H. Adachi, M. Roth, R. P. McDevitt, and D. M. Jacobowitz (1981) Peptides 2: 467-477). Previous studies (O'Donohue et al., 1981) demonstrated that MLIPs in rat brain probably differ chemically from porcine intestinal motilin (PIM), the first motilin peptide isolated. The possibility that this rat-pig difference represents a species difference was not examined in the previous study (O'Donohue et al., 1981), neither was the question of the cross-species distribution of MLIP. This study was initiated to examine brain MLIP distribution by RIA in three additional species: cow, pig, and guinea pig. The question of rat-pig species differences was addressed by characterizing MLIP in the brains of these species in comparison to PIM. By RIA, MLIPs were widely distributed in the brains of all species examined. MLIP concentration was highest in rat brain and lowest in pig brain. Some motilin antisera consistently detected less or no MLIPs in some brain regions of all species. Rat pituitary, pineal gland, and retina had substantially higher MLIP concentrations than did brain. MLIPs were abundant throughout the rat gastrointestinal tract and in some other peripheral organs.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1980

Actions of motilin on gastrointestinal motility and plasma immunoreactive motilin concentration in interdigestive and postprandial states.

Among biological actions of motilin on gastrointestinal motility, its action to induce phase III, activity front, of interdigestive myoelectric complex (IMC) appears to be of physiological significance. Synthetic motilin in a dose as little as 0.06 microgram/kg-h was shown to induce phase III in dog. A cyclic increase in fasting plasma immunoreactive motilin concentration (PIMC) occurred in phase III in dog and in a later part of phase II in man, suggesting strongly that there is an intimate relationship between cyclic increase in fasting PIMC and IMC. The observation also suggested that gastric acid secretion increases in phase II and phase III of IMC. The cyclic increase in the acid secretion may be related to a coincidental cyclic increase in PIMC. Ingestion of a meat meal results in a significant decrease in PIMC and abolishes the cyclic increase in PIMC, while IMC changes to digestive pattern after a meal. The significant decrease in PIMC is not attributed to the 3 known gut hormones including gastrin, octapeptide of CCK and secretin.

Animals↗
PubMed2002

Effects of SK-896, a new human motilin analogue ([Leu13]motilin-Hse), on postoperative ileus in dogs after laparotomy.

The effects of SK-896, a new human motilin analogue ([Leu13]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 microg/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.

Animals↗