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At least 19 recordsLinked to original sources
PubMed1976

[The synthesis of motilin, III: Purification and characterization of (13-norleucine) motilin and (13-leucine) motilin (author's transl)].

The preparation of the pure docosapeptide H-Phe-Val-Pro-I1e-Phe-Thr-Tyr-Gly-Glu-Leu-Gln-Arg-Nle-Glu-Glu-Lys-Glu-Arg-Asn-Lys-Gly-Gln-OH ([Nle13]motilin) and of the analogous [Leu13]motilin from the crude synthetic materials obtained after deblocking of the overall protected docosapeptide derivatives by means of trifluoroacetic acid is described. In a preliminary experiment the separation of crude [Nle13]-motilin into several components, some of which being indistinguishable by thin layer chromatography, was achieved by repeated ion-exchange chromatography on QAE-Sephadex A-25 and SP-Sephadex C-25. Subsequent characterization of some of the isolated side-products, using amino acid analysis as well as spectroscopic (UV, CD) and enzymatic methods, in comparison to the major product enabled conclusions on the reasons of their formation. The undesired formation of des-(Thr6 -Tyr7 Gly8)[Nle13] motilin and of [D-Phe5-Nle13]motilin could be avoided during the subsequent major synthesis of [Nle13] motilin and during the preparation of [Leu13] motilin by changing certain synthetic conditions and, respectively, by using a specially purified protected fragment of the sequence 1-8, being free of diastereomers. Single ion-exchange chromatography on SP-Sephadex C-25 was sufficient for the purification of the so obtained crude synthetic end-products.

Amino Acids↗
PubMed1976

[The synthesis of motilin, I: Preparation of the sequence fragments 9 - 22 of [13-norleucine]motilin and [13-leucine]motilin (author's transl)].

The syntheses of two suitably protected tetradecapeptides corresponding to the sequences 9 - 22 of [13-norlecucine] motilin [H-Glu(OBut)-Leu-Gln-Arg(HBr)-Nle-Glu(OBut)-Glu(OBut)-Lys(Boc)-Glu(OBut)-Arg(HBr-Asn-Lys(Boc)-Gly-Gln-OBu] and [13-leucine] motilin, respectively, are described. The two building blocks for the total syntheses of the motilin analogs were obtained by fragment-condensation of smaller units, prepared by stepwise procedure and corresponding to the sequences 18 - 22, 14 - 17, 12 - 13 (norleucine- and leucine-derivatives) and 9 - 11.

Amino Acid Sequence↗
PubMed1976

[The synthesis of motilin, II: Preparation of the complete sequences of [13-norleucine] motilin and [13-leucine] motilin (author's transl)].

Syntheses of two analogs of the intestinal hormone motilin containing in position 13 norleucine and leucine, respectively, are described. For this purpose a suitably protected octapeptide-derivative, corresponding to the sequence 1-8, was prepared and condensed with the tetradecapeptides 9-22 of [13-norleucine]-motilin and [13-leucine] motilin (described in the preceding paper) to give to overall protectdd docosapeptides Boc-Phe-Val-Pro-IIe-Phe-Thr-(But)-Tyr(But)-Gly-Glu(OBut)-Leu-Gln-Arg-(HBr)-Nle-Glu(OBut)-Glu(OBut)-Lys(Boc)-Glu-(OBut)-Arg(HBr)-Asn-Lys(Boc)-Gly-Gln-OBut and its 13-leucine analog.

Amino Acid Sequence↗
PubMed1984

Relationship between porcine motilin-induced migrating motor complex-like activity, vagal integrity, and endogenous motilin release in dogs.

Both the vagus nerve and motilin have been implicated in the initiation of phase III of the fasting migrating motor complex. To investigate the contribution of each, the effects of intravenous porcine motilin, vagosympathetic nerve blockade, and atropine were assessed. Intralumenal pressures of the lower esophageal sphincter, stomach, and upper small intestine, and plasma motilin levels were monitored. Porcine and canine motilin in plasma were distinguished by radioimmunoassay using two different antibodies. Injection of porcine motilin (75-370 pmol), initiated dose-dependent phase III-like motor activity in the lower esophageal sphincter, stomach, and small bowel if the vagi were intact; if the vagi were blocked, activity was initiated in the small bowel only. Moreover , a significant (p less than 0.001), dose-dependent peak in canine plasma motilin was observed after the onset of the induced motor activity when the vagi were intact or blocked, with plasma motilin peaks comparable to those occurring spontaneously. In both intact and vagally blocked dogs, atropine abolished both the spontaneous motor activity and associated rise in motilin level, and also abolished porcine motilin-induced activity. However, a diminished, but significant (p less than 0.01) peak in porcine motilin-induced canine motilin persisted in the presence of atropine. These results in dogs indicate that while spontaneous phase II motility in the upper gastrointestinal tract and phase III activity in the lower esophageal sphincter and stomach are dependent on vagally mediated excitatory pathways, spontaneous and induced phase III motor activity in the small intestine are dependent on nonvagal cholinergic innervation. Canine motilin release induced by porcine motilin is mediated primarily by a nonvagal cholinergic (muscarinic) pathway, with minor contributions from vagal noncholinergic, and nonvagal noncholinergic mechanisms. Because spontaneous or induced motilin release peaks well after the onset of phase III motor activity, it is unlikely that motilin is the primary factor responsible for initiation of the migrating motor complex in the dog. Motilin may, however, modulate motility produced by preexisting neural excitation.

Animals↗
PubMed1994

Motilin synthetic analogues and motilin receptor antagonists.

While studying the structure-activity characteristics of motilin with motilin synthetic analogues, two compounds, motilin 1-12 [CH2 NH]3-4 and motilin 1-12 [CH2 NH]10-11, showed high affinity for the motilin receptor combined to a weak contractile activity. The following data suggest that motilin 1-12 [CH2 NH]10-11 is a potent motilin receptor antagonist. It showed a high affinity for the motilin receptor present on membranes of rabbit antrum (pIC50: 8.24 +/- 0.08 for the analogue vs 8.96 +/- 0.02 for the native peptide). When tested in vitro on strips of rabbit duodenum, the dose-response curve to motilin 1-22 was displaced to the right with motilin 1-12 [CH2 NH]10-11 (pIC50: 8.91 +/- 0.06 in presence of saline versus 7.19 +/- 0.40 with the analogue). However, when injected i.v. in dogs, motilin 1-12 [CH2 NH]10-11 was undetectable in the peripheral blood, suggesting enzymatic degradation precluding its use in vivo.

Animals↗
PubMed1987

Comparative stimulation of motilin duodenal receptor by porcine or canine motilin.

Motilins purified from porcine and canine intestine differ in their amino acid composition in positions 7-8-12-13-14. We studied in vitro the contractile response of longitudinal duodenal muscles from various animals (guinea pig, rabbit, dog) to porcine and canine synthetic motilins. Both substances failed to elicit contraction of the guinea pig duodenum but were active and equally potent on rabbit muscle. In dogs, porcine motilin was inactive at the concentrations tested (up to 10(-4) M) whereas canine motilin induced duodenal contractions in a dose-response fashion (mean dose required to induce half-maximal response: 4.82 +/- 0.25 X 10(-5) M). The contraction generated by synthetic canine motilin (10(-5) M) was not influenced by atropine, hexamethonium, tetrodotoxin, naloxone, or sodium nitroprusside (all used at 10(-4) M) but was blocked by verapamil (10(-4)). Our study shows that species-related structural alterations in motilin molecules generate different bioactive capacities in some animal species, suggests that the middle portion of the molecule is important for its bioactive expression, suggests the presence of motilin receptors on canine duodenal muscle, and suggests that an influx of extracellular calcium is involved in the canine duodenal muscle contraction elicited by canine motilin.

Animals↗
PubMed1991

Motilin-immunoreactive cells in the duodenum, pyloric stomach and pancreas of caimans (Caiman latirostris and Caiman crocodilus, alligatorinae): a further comparison using region-specific motilin antisera.

Motilin-immunoreactive cells in the duodenum, pyloric stomach and pancreas of Caiman latirostris and Caiman crocodilus were investigated using region specific antisera for porcine and canine motilin molecules. Motilin-immunoreactive cells were found in the duodenum, pyloric stomach and pancreas of both caiman species. These cells were primarily open-type endocrine ones in the epithelium of the duodenum and pyloric stomach. Motilin-immunoreactive cells were observed in both the exocrine and endocrine portions of the pancreas, and frequently exhibited one or more cytoplasmic processes of variable length. Since motilin-immunoreactive cells do not cross-react with serotonin or any of the other pancreatic and gut hormones, they are considered to be cell type independent from any of the other known pancreatic or gut endocrine cells. The molecular similarity between caiman motilin and porcine and canine motilins and the heterogeneity of the motilin molecule in the caiman digestive system is discussed.

Alligators and Crocodiles↗
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↗
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↗
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↗
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↗