Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Incorporation of D-Pro9 into substance P related peptides is known to enhance neurokinin NK-2 receptor agonist potency and selectivity with respect to other neurokinin receptors. We now report that replacement of D-Trp9 by D-Pro9 in the nonselective neurokinin antagonist [Arg5,D-Trp7,9, Nle11]-SP(5-11) gave a partial agonist with NK-2 receptor selectivity. Further incorporation of Pro10 provided the weak but selective NK-2 antagonist Arg-Ala-D-Trp-Phe-D-Pro-Pro-Nle-NH2 (compound 4; NK-2 pKB = 5.9; NK-1 pKB = 4.7; NK-3 pKB less than 4.6). Addition of a suitable lipophilic N-terminal substituent (e.g. Boc, PhCO, cyclohexylcarbonyl) to this compound greatly enhanced NK-2 antagonist activity (compound 10, GR 83074; NK-2 pKB = 8.2), and combined with further optimization of the N-terminal amino acids, provided the extremely potent and selective NK-2 antagonist PhCO-Ala-Ala-D-Trp-Phe-D-Pro-Pro-Nle-NH2 (compound 34, GR 94800; NK-2 pKB = 9.6; NK-1 pKB = 6.4; NK-3 pKB = 6.0). Compounds of this class produced a potent inhibition of NK-2 agonist-induced bronchoconstriction in the anaesthetized guinea-pig.
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PMID:Highly potent and selective heptapeptide antagonists of the neurokinin NK-2 receptor. 132 7

To discover a novel and low molecular weight substance P (SP) antagonist we postulated that the essential binding domain of peptide ligands was only a small portion in the whole structure. On the basis of this assumption, we selected the known octapeptide SP antagonist D-Pro-Gln-Gln-D-Trp-Phe-D-Trp-D-Trp-Phe-NH2 (1) as a lead and synthesized its fragment tripeptides which were evaluated for their activity to block 3H-SP binding on guinea pig lung membranes. The protected tripeptide N alpha-[N alpha-[N alpha-(tert-butyloxycarbonyl)-L-glutaminyl]-N1-formyl-D-tryptophyl]- L-phenylalanine benzyl ester [Boc-Gln-D-Trp(CHO)-Phe-OBzl (4a)], corresponding to the Gln-D-Trp-Phe part of 1, exhibited 7-fold potent inhibitory activity in comparison with 1. Studies on structure-activity relationships revealed that the D-tryptophan, L-phenylalanine, and benzyl ester were quite important to maintain the high binding affinity. It was also indicated that 4a antagonized the SP-induced contraction of isolated guinea pig trachea strips (IC50 = 4.7 x 10(-6) M).
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PMID:Studies on neurokinin antagonists. 1. The design of novel tripeptides possessing the glutaminyl-D-tryptophylphenylalanine sequence as substance P antagonists. 137 65

A new hexapeptide analog of Substance P, containing a C-terminal thioamide group in the molecule [( Glp6, Mett11]SP6-11) was synthesized: Glp-Phe-Phe-Gly-Leu-Mett-NH2. Conversion to thioamide was accomplished from tert-butoxycarbonyl-L-methionine amide (Boc-Met-NH2) using Lawesson's Reagent. Its contracting activity on isolated guinea-pig ileum was considerably lower than that of [Glp6]SP6-11.
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PMID:Synthesis and some biological properties of the hexapeptide analog of substance P with a C-terminal thioamide group. 171 85

During the preparation of the NK-2 selective tachykinin antagonist MEN 10208 (Thr-Asp-Tyr-D-Trp-Val-D-Trp-D-Trp-Arg-NH2) and its analogs by the solid-phase method employing the Boc strategy routinely used in our laboratory, we encountered difficulties in the coupling of hydrophobic amino acids D-Trp and Val. To study the coupling problems several syntheses of MEN 10208 and analogs were carried out with different activation strategies. These syntheses yielded considerable amounts of deletion sequences even though a negative Kaiser test was obtained after each coupling. Inaccessibility of the free amino group of the growing peptide due to steric hindrance of the hydrophobic residues during coupling, and for the ninhydrin complex during the Kaiser test, may account, at least in part, for the unsatisfactory synthetics results and for the false-negative ninhydrin tests. Repetition of each synthesis with the Fmoc strategy on a newly developed DOD resin for peptide amides using the DCC/HOBt chemistry gave superior results in terms of the yield and purity of the crude peptides. Therefore, the Fmoc strategy appears to offer advantages over the Boc method for the preparation of these peptides containing hydrophobic amino acids.
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PMID:Solid-phase synthesis of neurokinin A antagonists. Comparison of the Boc and Fmoc methods. 185 Mar 90

Neurotensin (NT) endopeptidase (EC 3.4.24.16) has been purified about 800-fold from pig brain by four sequential chromatographic steps depending on ion-exchange and hydrophobic interactions. Two types of preparation were studied: one from a Triton X-100-solubilized membrane fraction, and the other from the soluble fraction containing 90% or more of the total activity in the homogenate. NT endopeptidase activity was monitored by high-precision liquid chromatography of the two peptide products, characterized as NT-(1-10) and NT-(1-8), resulting from cleavage of the Pro10-Tyr11 and Arg8-Arg9 bonds respectively. As purification proceeded, from both membranes and cytosol, the yield of the two products achieved a constant ratio of 5:1 and this ratio was reproduced in repeated purifications. However, a distinct peptidase which hydrolysed exclusively at the Arg8-Arg9 bond was partially resolved from NT endopeptidase by chromatography on hydroxyapatite, and this activity was further purified and assigned to endopeptidase-24.15 (EC 3.4.24.15). SDS/PAGE of both preparations of neurotensin endopeptidase revealed a major band of apparent Mr 75000, and treatment of the membrane-associated form with N-Glycanase gave no evidence that the enzyme was a glycoprotein. The membrane-associated and cytosol forms of NT endopeptidase activities, monitored for both NT-(1-10) and NT-(1-8) products, were compared in their responses to 1,10-phenanthroline, EDTA, dithiothreitol (DTT) and some synthetic site-directed inhibitors of endopeptidase-24.15 or peptidyl dipeptidase A. The effects revealed no significant differences between the two preparations, nor did the reagents discriminate between the activities generating the two NT fragments. The partially purified form of endopeptidase-24.15 was also included in this comparison: while some responses were similar, this peptidase was distinguishable in its activation by DTT and its relative resistance to inhibition by EDTA. Both forms of NT endopeptidase were found to hydrolyse other substrates, including Boc-Phe-Ala-Ala-Phe-4-aminobenzoate, bradykinin and substance P (these at faster rates than neurotensin), as well as dynorphin A-(1-8) and luliberin. The bonds hydrolysed in these neuropeptides, as well as in angiotensins I and II and alpha-neoendorphin, were defined. These studies confirm that NT endopeptidase is distinct from endopeptidase-24.15. They further show that the former is a soluble enzyme, not an integral membrane protein, that it is not peptide-specific and that it might be more appropriately named. enzyme, not an integral membrane protein, that it is not peptide-specific and
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PMID:Purification and properties of a neurotensin-degrading endopeptidase from pig brain. 190 21

A peptidase activity of rat diencephalon membranes, which acts on the C-terminal hexapeptide sequence of substance P, was characterized using the radiolabeled substrate N alpha-[( 125I]iododesaminotyrosyl)-substance P (6-11)-hexapeptide. This activity presents certain characteristics similar to those of the substance-P-degrading enzyme purified from human brain by Lee et al. [Eur. J. Biochem. 114, 315-327 (1981)]. It is inhibited by metal chelators and some thiol reagents, but is insensitive to inhibitors of serine proteases and aminopeptidases. The activity is different from angiotensin-converting enzyme and enkephalinase, since it is not affected by specific inhibitors of these enzymes. Substance P and substance P C-terminal fragments longer than the pentapeptide inhibited the degradation of the radiolabeled substrate with inhibition constants around 200 microM. Short fragments of the substance P sequence, such as Boc-Phe-Phe-OMe and Boc-Phe-Phe-Gly-OEt, were also found to inhibit the degradation of the substrate. When the metal-chelating hydroxamic acid moiety was attached to the carboxyl terminus of these short peptides, potent inhibitors of the substance-P-degrading activity were obtained, with inhibition constants in the micromolar range. The most potent of these compounds, iododesaminotyrosyl-Phe-Phe-Gly-NHOH (IBH-Phe-Phe-Gly-NHOH), is a competitive inhibitor, with a Ki value of 1.9 microM. The degradation of substance P by rat diencephalon slices was inhibited to the same extent (40-50%) by IBH-Phe-Phe-Gly-NHOH (20 microM) and by phosphoramidon (1 microM). A combination of both reagents reduced the degradation rate by 75-80%, suggesting that both enkephalinase and the substance-P-degrading activity are involved in the metabolism of substance P in this preparation. IBH-Phe-Phe-Gly-NHOH seems to be quite specific for the latter enzyme, since at a high concentration (0.1 mM) it did not affect the degradation of the radiolabeled substrate by alpha-chymotrypsin, papain, or thermolysin.
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PMID:Inhibition of substance P degradation in rat brain preparations by peptide hydroxamic acids. 241 Feb 67

The undecapeptide substance P (SP) was tested for its ability to promote human monocyte chemotaxis in a modified Boyden chamber assay. Substance P was found to be active in this assay system with an ED50 for chemotactic effect of approximately 10(-13) M. This response was shown to be chemotactic in nature since a concentration gradient of attractant was required for maximal effect. Other substance P analogs tested showed a rank order of potency of substance P greater than or equal to SP(3-11) greater than SP(8-11) approximately equal to SP(9-11) much greater than SP(1-9), SP, free acid. These results suggest that chemotactic responsiveness is largely encoded in the C-terminus of the molecule. The relative potency order for SP and its analogs in promoting monocyte chemotaxis correlates well with their potencies in displacing labeled SP when binding sites are directly measured in other tissues, such as rat brain or human lymphocytes. Additionally, the chemotactic effects of SP could be partially reversed by the weak antagonist [D-Arg1, D-Pro2, D-Trp7,9, Leu11]-SP. The N-formyl peptide receptor antagonist, t-Boc-Phe-Leu-Phe-Leu-Phe, did not block SP-mediated chemotaxis, further indicating the specificity of these effects. These results suggest the existence of a specific substance P receptor on human monocytes which directs this chemotactic response. The ability of monocytes to respond chemotactically to SP may be relevant to the enhancing effects of SP in arthritis or other inflammatory diseases.
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PMID:Substance P receptor-mediated chemotaxis of human monocytes. 241 6

Two solution syntheses of cyclo(11----5 epsilon)-[Lys5]substance P-(5-11) (CLP) were carried out. The first synthesis involved the stepwise elongation of the peptide chain starting from glycine tert-butyl ester. At the stage of hexapeptide deprotection, the cleavage of Boc and But groups was accompanied by tert-butylation of the Met residue. Cyclization was carried out via a pentafluorophenyl ester intermediate. The benzyloxycarbonyl-cyclopeptide (Z-CLP) formed was deprotected by catalytic transfer hydrogenation. A (3 + 4) block coupling strategy was used in course of the repeated preparation of the linear precursor of CLP. Optimization of the cyclization and subsequent deprotecting stages lead to increased yields and facilitated the synthetic procedure. Z-CLP was found to possess myotropic activity on isolated guinea pig ileum (alpha = 0.55 +/- 0.18; pD2 = 7.97 +/- 0.20), whereas CLP was inactive in these experiments. Z-CLP causes a slight two-phase effect on arterial pressure in rats, CLP being inactive. Similar to substance P, CLP displays an antidepressant-like effect in mice as indicated by the swimming test.
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PMID:[Cyclic analogs of substance P. I. Cyclo(11----epsilon 5)-[Lys5] substance P-(5-11)]. 245 93

Pentapeptides X-D.Trp-Phe-D.Trp-Leu-Y-NH2 (X = H, Boc, parahydroxyphenylacetyl, Y = Met,Leu,Nle,Phe) were tested as antagonists against Substance P and against a specific agonist of the muscular receptor of neurokinins on the guinea-pig ileum. Weak antagonist or agonist activities could be observed with the free or the Boc-protected pentapeptides whilst the acylated compounds could be compared favorably with the best antagonists already described.
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PMID:N-acylated pentapeptides antagonists of substance P on guinea-pig ileum. 246 99

N-formyl-methionyl-leucyl-phenylalanine (FMLP), a synthetic analogue of bacterial chemotactic peptide, may play a role in airway hyperresponsiveness, and is cleaved by neutral endopeptidase-24.11 (enkephalinase). To determine the effect of FMLP on parasympathetic contraction of airway smooth muscle and its modulation by endogenous enkephalinase, we studied isolated rabbit tracheal ring segments under isometric conditions in vitro. FMLP did not cause muscle contraction, but it potentiated the contractile response to electrical field stimulation (EFS) in a dose-dependent fashion, with the maximal increase from the baseline response being 59.8 +/- 6.2% (mean +/- S.E.M., P less than 0.001), an effect that was abolished by t-Boc-Phe-Leu-Phe-Leu-Phe, partially inhibited by pyrilamine, but not by phentolamine or [D-Pro2,D-Trp7,9]substance P. In contrast, the contractile response to administered acetylcholine was not affected by FMLP. Pretreatment of tissues with thiorphan, an enkephalinase inhibitor, further potentiated the effect of FMLP on the EFS-induced contraction. These results suggest that FMLP facilitates cholinergic neurotransmission in rabbit airway smooth muscle probably by increasing acetylcholine release, and that this effect may be modulated by enkephalinase in the airway.
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PMID:The effect of N-formyl-methionyl-leucyl-phenyl-alanine on cholinergic neurotransmission and its modulation by enkephalinase in rabbit airway smooth muscle. 255 8


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