Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P01178 (oxytocin)
15,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

As part of a program in which we are attempting (a) to delineate the structural features at positions 1-9 in our previously reported antidiuretic antagonists required for antidiuretic antagonism and (b) to obtain analogues with enhanced antiantidiuretic potency and/or selectivity, we have synthesized 14 new analogues of the antidiuretic antagonist [1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid),2-D-phenylalanine,4-valine]arginine-vasopressin [d-(CH2)5-D-Phe2VAVP), in which the valine residue at position 4 was replaced by the following L-amino acids and glycine: Ile, Abu, Thr, Ala, Gln, Lys, Cha, Nle, Nva, Phe, Leu, Gly, Tyr, and Pro. These analogues are 1, d-(CH2)5-D-Phe2,Ile4AVP; 2, d(CH2)5-D-Phe2,Abu4AVP; 3, d(CH2)5-D-Phe2,Thr4AVP; 4, d(CH2)5-D-Phe2,Ala4AVP;5, d(CH2)5-D-Phe2AVP; 6, d(CH2)5-D-Phe2,Lys4AVP; 7, d(CH2)5-D-Phe2,Cha4AVP; 8, d(CH2)5-D-Phe2,Nle4AVP; 9, d(CH2)5-D-Phe2,Nva4AVP; 10, d(CH2)5-D-Phe2,Phe4AVP; 11, d(CH2)5-D-Phe2,Leu4AVP; 12, d(CH2)5-D-Phe2,Gly4AVP; 13, d(CH2)5-D-Phe2,Tyr4AVP; 14, d(CH2)5-D-Phe2,Pro4AVP. The protected intermediates required for the synthesis of all of these peptides were prepared by the solid-phase method and cleaved from the resin by ammonolysis. Following deblocking with Na in NH3 and oxidizing with K3[Fe(CN)6], each peptide was purified on Sephadex G-15 in a two-step procedure using 50% HOAc and 0.2 M HOAc as eluants. Analogues 1-14 were tested for agonistic and antagonistic activities by antidiuretic, vasopressor, and oxytocic assays in rats. Analogues 1, 2, and 4-6 exhibit no detectable antidiuretic agonistic activity. All analogues, with the exception of the Pro4-containing analogue, are antidiuretic antagonists. Their antiantidiuretic pA2 values are as follows: 1, 8.24 +/- 0.08; 2, 7.96 +/- 0.07; 3, 7.62 +/- 0.09; 4, 7.52 +/- 0.03; 5, 7.21 +/- 0.07; 6, 7.22 +/- 0.12; 7, 7.19 +/- 0.08; 8, 7.12 +/- 0.09; 9, 6.99 +/- 0.06; 10, 6.07 +/- 0.11; 11, 6.07 +/- 0.11; 12, 5.85 +/- 0.05; 13, approximately 5.57; 14, a weak agonist (0.004 U/mg). Analogues 1-14 also antagonize the vascular responses to arginine-vasopressin (AVP) and the in vitro oxytocic responses to oxytocin. Analogues 1, 2, 3, and 5 have also been shown to antagonize the in vivo oxytocic responses to oxytocin. Five of these analogues (1, 2, 3, 6, and 7) exhibit enhanced antiantidiuretic/antivasopressor selectivity. d(CH2)5-D-Phe2,Lys4AVP and other position-4 analogues with side-chain functional groups may be useful covalent ligands with which to probe the structural characteristics of AVP renal and vascular receptors. With an antiantidiuretic "effective dose" of 0.46 +/- 0.07 nmol/kg and a pA2 value of 8.24 +/- 0.08, d(CH2)5-D-Phe2,Ile4AVP (1) appears to be the most potent antidiuretic antagonist reported to date.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Potent antagonists of the antidiuretic responses to arginine-vasopressin based on modifications of [1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid),2-D- phenylalanine,4-valine]arginine-vasopressin at position 4. 663 16

An oxytocin fragment which accumulated during the incubation of oxytocin with brain synaptic membranes was chemically characterized as the hexapeptide pGlu-Asn-Cys(Cys)-Pro-Leu-Gly-NH2 [( pGlu4, Cyt6]OXT-(4-9]. This peptide was approximately a hundred times more potent than oxytocin in attenuating memory consolidation as tested in a passive avoidance test situation; the dose-response relationship was bell-shaped. The des-glycinamide derivative [pGlu4, Cyt6]OXT-(4-8) was nearly as active, but showed a linear dose-response relationship. The data indicate that oxytoxin can act as precursor for potent behaviourally active neuropeptides.
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PMID:Oxytocin is a precursor of potent behaviourally active neuropeptides. 665 55

The nonapeptide hormone oxytocin-like arginine-vasopressin (AVP) is synthesized as part of a larger precursor polypeptide. The precursor also includes the neurophysin molecule with which the hormone is associated in the neurosecretory granules of the hypothalamo-pituitary tract. A protein of molecular weight (Mr) approximately 20,000 has been isolated from supraoptic nuclei of rat hypothalami which, after tryptic cleavage, released a neurophysin-like molecule of Mr approximately 10,000 and an oligopeptide related to oxytocin. This result was complemented by in vitro translation of bovine hypothalamic mRNA. Among the primary translation products a single polypeptide of Mr approximately 16,500 was shown to contain antigenic determinants recognized by specific antisera against bovine neurophysin I and oxytocin. Here we report the amino acid sequence of the bovine oxytocin-neurophysin I (OT-NpI) precursor which was derived from sequence analysis of the cloned cDNA. As is the case for the bovine arginine-vasopressin-neurophysin II (AVP-NpII) precursor, the signal sequence of the OT-NpI precursor is immediately followed by the nonapeptide hormone which is connected to neurophysin I by a Gly-Lys-Arg sequence. A striking feature of the nucleic acid sequence is the 197-nucleotide long perfect homology with the AVP-NpII precursor mRNA sequence encoding the conserved middle part of neurophysins I and II.
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PMID:Deduced amino acid sequence from the bovine oxytocin-neurophysin I precursor cDNA. 668 26

A post-proline cleaving enzyme [post-proline endopeptidase: EC 3.4.21.26] was purified from lamb brain by a series of column chromatographies on DEAE-Sephadex, hydroxyapatite and Sephadex G-150. The purified enzyme appeared homogeneous on disc gel and sodium dodecyl sulfate (SDS) gel electrophoreses. The enzyme was most active at pH 7.0 with carbobenzoxy-Gly-Pro-beta-naphthylamide (Z-Gly-Pro-2-NNap) as a substrate and catalyzed the hydrolysis of oxytocin, vasopressin, thyrotropin releasing hormone (TRH), substance P, luteinizing hormone releasing hormone (LH-RH), and angiotensin at the carboxyl side of their proline residues, except for the Pro2-Lys3 bond in substance P. From the results of subsite mapping using synthetic peptides, five subsites, S3 to S2', for substrate interaction with the enzyme were deduced to be present, and high stereospecificity was observed at S2, S1, and S1'. The isoelectric point of the enzyme was at pH 4.9, and the molecular weights estimated by gel filtration and SDS gel electrophoresis were 74,000 and 77,000, respectively. The enzyme was markedly inhibited by diisopropylphosphoro fluoridate (DFP), carbobenzoxy-Gly-Pro-chloromethyl ketone (Z-Gly-Pro-CH2Cl), p-chloromercuribenzoate (PCMB), Hg2+, and Cu2+ ions. These enzymatic and protein chemical properties of post-proline cleaving enzyme from lamb brain closely resemble those of the lamb kidney enzyme, except for the molecular weight. In the present work, however, we decided that the molecular weight of the enzyme from lamb kidney was also 74,000, which is different from that reported previously (J. Biol. Chem. 251, 7593 (1976) but is in accord with the value of post-proline cleaving enzyme from lamb brain.
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PMID:Post-proline cleaving enzyme from lamb brain. 702 30

Oxytocin was synthesized via the solid-phase method using dehydroalanine as pseudo-protecting group of the carboxyl-terminal as well as the omega-amide functions of asparagine and glutamine in endo-position. Starting with Boc-Gly-Dha-resin and using Boc-L-Asp(Dha-NHEt)-OH and Boc-L-Glu(Dha-NHEt)-OH as precursors of asparagine and glutamine, respectively, oxytocin was assembled in stepwise manner under solid phase synthesis conditions. Treatment of the protected [Glu(Dha-NHEt)4, Asp(Dha-NHEt)5]-oxytocin-Dha-resin with 1 n HCl in glacial acetic acid in the presence of 3 equiv. water removed the peptide from the support with the simultaneous formation of the asparagine and glutamine residues to give the protected nonapeptide amide: Cbz-Cys(Bzl)-Tyr(Bzl)-Ile-Gln-Asn-Cys(Bzl)-Pro-Leu-Gly-NH2, which was deprotected with sodium in liquid ammonia and then oxidized with diiodoethane to give oxytocin. After purification by gel chromatography and countercurrent distribution, the product displayed the chemical and physical properties and oxytocic activity (533 +/- 301U/mg) of a standard oxytocin preparation.
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PMID:Solid-phase synthesis of peptides via alpha, beta-unsaturated amino acids: oxytocin, simultaneous incorporation of amide functions in COOH-terminal and endo-positions. 711 12

Intracerebroventricular administration of fragments of [arginine8]-vasopressin (AVP) such as AVP1-6 and AVP7-9 attenuated the pressor response evoked by electrical stimulation of the mesencephalic reticular formation in urethane-anaesthetized rats. Oxytocin (OXT) and the fragment OXT7-9 were also active, although OXT1-6 did not affect the pressor response. These peptides did not influence the bradycardia accompanying the rise in blood pressure, nor the basal blood pressure. The inhibition of the pressor response was shown for OXT7-9 to be dose-dependent up to 25 ng. These data suggest that oxytocin, vasopressin and some neuropeptide fragments have an inhibitory role in the regulation of blood pressure. Both the covalent pressinoic ring structure and the C-terminal linear portion of vasopressin contain active sites, while the activity of oxytocin appears to be present in the C-terminal tripeptide Pro-Leu-Gly.
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PMID:Inhibition of centrally-evoked pressor responses by neurohypophyseal peptides and their fragments. 715 15

The vasotocin-like biological activity detected in an extract (E5 fraction) of bovine pineal gland was found not to be due to the presence of vasotocin, vasopressin or oxytocin. The data obtained by means of bio- and radioimmunoassays suggest that the peptide responsible for this biological activity, however, possess the same Pro-Arg-Gly(NH2) tripeptidic carboxy-terminal end as vasotocin.
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PMID:The vasotocin-like biological activity present in the bovine pineal is due to a compound different from vasotocin. 728 31

17O was introduced into the respective alpha- and gamma-COOH groups of Boc-Gly and Boc-Glu by saponification of the corresponding O-methyl esters with 1N NaOH in H2 17O. Other 17O enriched Boc-amino acids were prepared by acid catalyzed exchange into the amino acid alpha-COOH group followed by t-butyloxycarbonylation with t-butyl S-4, 6-dimethylpyrimidin-2-ylthio carbonate. Final enrichment, by approximately three orders of magnitude over natural abundance, was 60-100% of the possible maximum. The synthesis of [17O]-Gly-Ala, [17O]-Gly-Leu and [17O]-Gly-Glu by DCC/HBT mediated coupling of Boc-Gly-[17O]-alpha-COOH with amino acid-O-t-butyl esters followed by deprotection with HCl/EtOAc proceeded without undue loss of the isotope. Boc-[17O]-Pro-Leu-Gly-NH2 was prepared by a similar procedure. [Tyr2-17O]-, [Pro7-17O]- and [Gly4-17O]-oxytocin were synthesized using solid phase support. 17O-chemical shifts of synthetic intermediates and of the final products were as expected for each functional group. Linewidth data correlate with the molecular weights of the compounds prepared.
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PMID:Labeling of amino acids and peptides with isotopic oxygen as followed by 17O-N.M.R. 734 24

An endo-acting proline-specific oligopeptidase (prolyl oligopeptidase [POPase], EC 3.4.21.26) was purified to homogeneity from the Triton X-100 extracts of cells of Treponema denticola ATCC 35405 (a human oral spirochete) by a procedure that comprised five successive fast protein liquid chromatography steps. The POPase is a cell-associated 75- to 77-kDa protein with an isoelectric point of ca. 6.5. The enzyme hydrolyzed (optimum pH 6.5) the Pro-pNA bond in carbobenzoxy-Gly-Pro-p-nitroanilide (Z-Gly-Pro-pNA) and bonds at the carboxyl side of proline in several human bioactive peptides, such as bradykinin, substance P, neurotensin, angiotensins, oxytocin, vasopressin, and human endothelin fragment 22-38. The minimum hydrolyzable peptide size was tetrapeptide P3P2P1P'1, while the maximum substrate size was ca. 3 kDa. An imino acid residue in position P1 was absolutely necessary. The hydrolysis of Z-Gly-Pro-pNA was potently inhibited by the following, with the Ki(app) (in micromolar) in parentheses: insulin B-chain (0.7), human endothelin-1 (0.5), neuropeptide Y (1.7), substance P (32.0), T-kinin (4.0), neurotensin (5.0), and bradykinin (16.0). Chemical modification and inhibition studies suggest that the POPase is a serine endopeptidase whose activity depends on the catalytic triad of COOH ... Ser ... His but not on a metal. The amino acid sequence around the putative active-site serine is Gly-Gly-Ser-Asn-Pro-Gly. The enzyme is suggested to contain a reactive cysteinyl residue near the active site. Amino acid residues 4 to 24 of the first 24 N-terminal residues showed a homology of 71% with the POPase precursor from Flavobacterium meningosepticum and considerable homology with the Aeromonas hydrophila POPase. The ready hydrolysis of human bioactive peptides at bonds involving an imino acid residue suggests that enzymes like POPase may contribute to the chronicity of periodontal infections by participating in the peptidolytic processing of those peptides.
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PMID:An endo-acting proline-specific oligopeptidase from Treponema denticola ATCC 35405: evidence of hydrolysis of human bioactive peptides. 752 1

1. Modulatory effects of the four molluscan neuroactive peptides. FMRFamide (Phe-Met-Arg-Phe-NH2), APGW-amide (Ala-Pro-Gly-Trp-NH2), oxytocin and [SER2]-Mytilus inhibitory peptide ([SER2]-MIP) (Gly-Ser-Pro-Met-Phe-Val-NH2) were examined on the inward current (Iin) caused by achatin-I (Gly-D-Phe-Ala-Asp), which has been isolated from the Achatina ganglia. 2. Two Achatina giant neurone types, v-RCDN (ventral-right cerebral distinct neurone) and PON (periodically oscillating neurone), were used. Achatin-I was applied locally to the neurone tested by brief pneumatic pressure ejection, and the other molluscan neuroactive peptides were perfused around the ganglia. 3. FMRFamide, perfused at 3 microM, suppressed markedly the Iin elicited by the achatin-I of both v-RCDN and PON. APGW-amide at 3 microM also suppressed the Iin of v-RCDN, but did not affect that of PON. Oxytocin at 1 microM suppressed the Iin of PON, but did not affect that of v-RCDN. [Ser2]-MIP at 3 microM did not affect the Iin of v-RCDN. 4. The dose-response curves of FMRFamide, APGW-amide and oxytocin, indicated that their respective suppressive effects on the Iin of achatin-I were dose-dependent, and that APGW-amide was slightly more potent than the other peptides. The dose (pressure duration)-response curves of achatin-I (1 kg/cm2, 10(-3) M, 5 min interval), obtained by varying the duration of the achatin-I pressure ejection, were measured in the presence and absence of each of the three peptides.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Suppressing effects of neuroactive peptides on the inward current caused by achatin-I, an Achatina endogenous peptide. 754 26


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