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

1. Aminopeptidase Ey, purified from the egg yolk of the hen (Gallus gallus domesticus), was studied for its specificity against oligopeptides at pH 7.5. The enzyme has a broad specificity for amino acid residues at P1 position. 2. The enzyme hydrolyzed N-terminal Xaa-Pro bonds in chicken brain peptide (Leu-Pro-Leu-Arg-PheNH2), substance P fragment 1-4 (Arg-Pro-Lys-Pro) and bradykinin fragment 1-5 (Arg-Pro-Pro-Gly-Phe), but did not hydrolyze substance P (Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-MetNH2) or bradykinin (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg). 3. The enzyme released proline from Pro-Phe-Gly-Lys, while it was unable to release proline from melanocyte, stimulating the hormone release-inhibiting factor (Pro-Leu-GlyNH2) and schistoFMRF-amide (Pro-Asp-Val-Asp-His-Val-Phe-Leu-Arg-PheNH2).
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PMID:Substrate specificity of aminopeptidase Ey from hen's (Gallus domesticus) egg yolk. 768 60

The mechanism of action of the tachykinin NK2 receptor antagonists, SR 48968 ((S)-N-methyl-N[4-acetylamino-4-phenyl-piperidino)-2-(3,4- dichlorophenyl)butyl]benzamide) and MEN 10,627 (cyclo[(Met-Asp-Trp-Phe-Dap-Leu) cyclo (2 beta-5 beta)]), was compared in the guinea-pig isolated gallbladder and circular muscle of proximal colon by using neurokinin A and [beta Ala8]neurokinin A-(4-10) as agonists. The experiments performed with colon were in the presence of the tachykinin NK1 receptor-selective antagonist, (+/-)-CP-96,345 ([2-(diphenylmethyl)-N-[(2-methoxyphenyl)-methyl]-1- azabicyclo[2,2,2]octan-3-amine]). SR 48968 caused an insurmountable antagonism of tachykinin NK2 receptor-mediated contraction in both preparations; its blockade was essentially irreversible, since it was not reversed by washout (up to 2 h) and was increased by prolonging the incubation from 15 to 120 min. In contrast, MEN 10,627 produced simple competitive antagonism, which was time-independent and fully reversible in both preparations. In both preparations, the simultaneous administration of SR 48968 and MEN 10,627 produced an intermediate antagonism of the responses to the agonists, as compared to the antagonism produced by each antagonist alone. The present results are discussed in the light of the reported interaction of SR 48968 with tachykinin NK2 receptors at a recognition epitope distinct from that of agonist(s).
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PMID:Different mechanism of tachykinin NK2 receptor blockade by SR 48968 and MEN 10,627 in the guinea-pig isolated gallbladder and colon. 769 94

The antibronchospastic activity against acetylcholine, antigen, histamine plus platelet-activating factor (PAF) or the selective tachykinin neurokinin (NK)1 and NK2 receptor agonists of the novel tachykinin NK2 receptor antagonist, MEN10,627 (cyclo(Met-Asp-Trp-Phe-Dap-Leu)cyclo(2 beta-5 beta)), was studied in anesthetized guinea-pigs. MEN10,627 (30-100 nmol/kg i.v.) reduced in a dose-dependent manner the bronchospasm induced by the tachykinin NK2 receptor agonist [beta Ala8]neurokinin A-(4-10) and the effect of the highest dose lasted up to 5 h from its administration. Conversely, airway constriction induced by the NK1 receptor agonist [Sar9]substance P sulfone or acetylcholine was unaffected by MEN10,627 up to a dose of 3 mumol/kg i.v. In animals sensitized with ovalbumin and pretreated with the endopeptidase inhibitor phosphoramidon, the aerosolized antigen produced a bronchospasm which was inhibited by MEN10,627 (30-100 nmol/kg i.v.) but not by the tachykinin NK1 receptor antagonist, (+/-)-CP96,345 ([2R,3R-cis- and [2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)-methyl]-1- azabicyclo[2.2.2]octan-3-amine]) (3 mumol/kg i.v.). Both MEN10,627 (30-100 nmol/kg i.v.) and (+/-)-CP96,345 (30-300 nmol/kg i.v.) reduced the PAF-induced hyperresponsiveness to histamine, without affecting the hypotension induced by PAF or the bronchospasm induced by histamine in guinea-pigs not exposed to PAF, showing the involvement of both tachykinin NK1 and NK2 receptors in this model. In summary, MEN10,627 behaves as a potent, selective and long-lasting tachykinin NK2 receptor antagonist in vivo. Further, tachykinin NK2 receptors could be activated during allergic responses and in the development of airway hyperresponsiveness.
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PMID:Antibronchospastic activity of MEN10,627, a novel tachykinin NK2 receptor antagonist, in guinea-pig airways. 773 6

A series of cyclic pseudopeptides of the formula cyclo(Leu psi[CH2NH]Xaa-Gln-Trp-Phe-beta Ala), where Xaa represents the residue of an alpha-amino acid, has been synthesized in order to establish the role of the Xaa side chain for tachykinin NK-2 receptor antagonist activity. Syntheses have been carried out in solid phase with either Fmoc or Boc strategy. The antagonist potency on NK-2 receptors in the hamster isolated trachea (HT) and the rabbit isolated pulmonary artery (RPA) bioassays increases with Xaa lipophilicity; cyclo(Leu psi[CH2NH]Cha-Gln-Trp-Phe-beta Ala) and cyclo(Leu psi[CH2NH]Asp(NHBzl)-Gln-Trp-Phe-beta Ala) resulted in being the two most active antagonists (pA2 = 9.06 and 9.26 on HT, respectively). A significant linear correlation was found between pA2 values determined in HT and RPA bioassays and capacity factors measured in reversed phase HPLC. The comparison between the biological activities of cyclic hexapeptides containing or not containing the aminomethylene moiety proved the crucial role of the pseudopeptide bond for determining high antagonist potency at the NK-2 receptor.
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PMID:Influence of lipophilicity on the biological activity of cyclic pseudopeptide NK-2 receptor antagonists. 793 90

We describe the in vitro and in vivo pharmacological properties of MEN 10,627 or cyclo(Met-Asp-Trp-Phe-Dap-Leu)cyclo(2 beta-5 beta), the first example of a polycyclic peptide tachykinin NK2 receptor antagonist. MEN 10,627 is endowed with high affinity for NK2 receptor expressed in various species with pKB values ranging between 10.1 (hamster trachea) and 8.1 (rabbit pulmonary artery). The antagonism is of competitive type in both functional and radioligand binding assays. A 100- to 10,000-fold selectivity was found vs. NK1 or NK3 receptors expressed in various species. As an NK2 receptor antagonist, MEN 10,627 is 10- to 100-fold more potent than the monocyclic peptide antagonist L 659,877 or cyclo(Met-Gln-Trp-Phe-Gly-Leu). At the hamster NK2 receptor, MEN 10,627 is about 30-fold more potent than the nonpeptide NK2 receptor antagonist SR 48,968 [(S)-N-methyl-N[4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl) butyl]benzamide], whereas the converse is true for the rabbit NK2 receptor. Furthermore, MEN 10,627 is, up to micromolar concentrations, devoid of antagonist properties toward a wide range of transmitters of both peptide and nonpeptide nature. In urethane-anesthetized rats in vivo, MEN 10,627 (10-100 nmol/kg i.v.) produced long-lasting inhibition of contraction of the urinary bladder and duodenum produced by i.v. administration of the NK2 receptor agonist [beta Ala8]NKA(4-10), without affecting the responses produced by i.v. administration of the NK1 receptor agonist [Sar9]SP sulfone or acetylcholine. In anesthetized rats, both MEN 10,627 and SR 48,968 blocked urinary bladder contraction induced by the NK2 receptor agonist after intravenous, intranasal or intraduodenal administration. Equieffective doses of MEN 10,627 producing about 50% inhibition of the response to [beta Ala8]NKA(4-10) in the rat urinary bladder in vivo, were 0.01, 0.03 and 3 mumol/kg after intravenous, intranasal and intraduodenal administration, respectively. The corresponding doses of SR 48,968 were 0.03, 0.1 and 1 mumol/kg, after intravenous, intranasal and intraduodenal administration, respectively. In conclusion, MEN 10,627 is a potent and selective NK2 receptor antagonist, endowed with high potency and long duration of action in vivo, which is not restricted to parenteral administration.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:MEN 10,627, a novel polycyclic peptide antagonist of tachykinin NK2 receptors. 799 62

Using radioimmunoassays for mammalian tachykinins, peptides with substance P-like immunoreactivity and neurokinin A-like immunoreactivity were identified in an extract of the brain of the longnose skate, Raja rhina (elasmobranch) but only a peptide with neurokinin A-like immunoreactivity was identified in the brain of the sea lamprey, Petromyzon marinus (agnathan). The primary structure of the skate peptide with substance P-like immunoreactivity (Ala-Lys-His-Asp-Lys-Phe-Tyr-Gly-Leu-Met-NH2) shows one amino acid substitution (Phe3-->His) compared with scyliorhinin I, previously isolated from dogfish brain and gut. The skate neurokinin A-related peptide (His-Lys-Leu-Gly-Ser-Phe-Val-Gly-Leu-Met-NH2) shows two substitutions (Thr3-->Leu and Asp4-->Gly) compared with mammalian neurokinin A. Although the COOH-terminus of the lamprey tachykinin (Arg-Lys-Pro-His-Pro-Lys-Glu-Phe-Val-Gly-Leu-Met-NH2) resembles neurokinin A, the presence of the strongly conserved Lys/Arg-Pro-Xaa-Pro motif at the NH2-terminus of the peptide indicates greater structural similarity with substance P. The additional arginine residue at position 1 in the peptide suggests that the lamprey is utilizing a site of posttranslational processing in the tachykinin precursor that is different from the equivalent site in mammalian and other lower vertebrate preprotachykinin(s).
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PMID:Novel tachykinins from the brain of the sea lamprey, Petromyzon marinus, and the skate, Raja rhina. 801 73

Receptors for tachykinins and the signaling pathway to which they are coupled were characterized in dispersed muscle cells from the longitudinal muscle layer of the rat intestine. A technique of receptor protection whereby selective agonists and antagonists were used to protect one receptor while other receptors were inactivated with N-ethylmaleimide enabled each tachykinin receptor type to be identified separately. Protection of neurokinin (NK)-1 receptors with the selective NK-1 agonist, substance P methylester, or antagonist, GR-82,334 (Glp-Ala-Asp-Pro-Asn-Lys-Phe-Tyr-D-Pro[spiro-gamma-lactam]Leu-Trp-NH2), preserved the contractile response and increase in cytosolic-free Ca++ ([Ca++]i) induced by substance P methylester only; protection of NK-2 receptors with the selective NK-2 agonist, beta-[Ala8]NKA(4-10), or the selective NK-2b antagonist, L-659,877 [cyclo(Leu-Met-Gln-Trp-Phe-Gly)], preserved the contractile response and increase in [Ca++]i induced by beta-[Ala8]NKA(4-10) only; and protection of NK-3 receptors with the selective NK-3 agonist, senktide succinyl-[Asp6,MePhe8]substance P(6-11), preserved the contractile response and increase in [Ca++]i induced by succinyl-[Asp6,MePhe8]substance P(6-11) only. When used as a protective agent, the NK-2a antagonist, MEN-10,376 (H-Asp-Tyr-D-Trp-Val-D-Trp-D-Trp-Lys-NH2), did not preserve the response to any tachykinin agonist. Protection of NK-1, NK-2 and NK-3 receptors preserved fully the responses to the preferential endogenous agonists, substance P, NKA and NKB, respectively, but they also preserved in part (30-40%) the responses to the nonpreferential agonists. Because substance P and NKA are coreleased from the same precursor in intestinal muscle tissue, the pattern implied the existence of considerable spareness in the contractile response of muscle cells to tachykinins. Studies on dispersed circular muscle cells using selective tachykinin agonists as protective agents confirmed the presence of three tachykinin receptor types. The results demonstrate the coexistence of NK-1, NK-2b and NK-3 receptors on muscle cells of rat intestine that are preferentially activated by substance P, NKA and NKB, respectively, and are coupled separately to one signaling pathway mediating contraction.
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PMID:Coexistence of three tachykinin receptors coupled to Ca++ signaling pathways in intestinal muscle cells. 803 20

Hepatitis C virus (HCV) encodes a polyprotein that is processed to produce the structural and nonstructural proteins of the virus. Nonstructural protein 3 (NS3) is a serine proteinase that cleaves the polyprotein to release the NS4A, NS4B, NS5A, and NS5B proteins. To characterize the substrate specificity of NS3, we synthesized by in vitro translation the polyprotein NS2*-NS3-NS4*P that includes 70% of the NS2 protein, the complete NS3 protein, and 25% of the NS4 protein region attached to substance P, an epitope tag. We demonstrated that NS3 cleaves at the NS3/NS4A junction to release the NS4*P protein. Subsequently, we used this reaction to evaluate the importance of conserved amino acids that flank the NS3/NS4A junction. We replaced amino acids in the P6, P1, and P1' positions of the scissile bond of this junction using site-directed mutagenesis. When the P6 aspartic acid was changed to asparagine, lysine, or serine, NS3-mediated cleavage occurred. When threonine in the P1 position was replaced with other polar amino acids or with amino acids having aliphatic side chains, cleavage occurred, although it was not detected when arginine or tyrosine was present. Replacement of serine in the P1' position with other polar amino acids, with amino acids having aliphatic side chains, or with arginine resulted in NS3-mediated cleavage. Thus, since fewer amino acids in the P1 position supported cleavage than in the P6 or P1' positions, the P1 position of the scissile bond may play a more important role in defining the substrate specificity of the HCV NS3 proteinase.
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PMID:Substrate specificity of the NS3 serine proteinase of hepatitis C virus as determined by mutagenesis at the NS3/NS4A junction. 809 50

The tachykinin (NK2) receptor-mediating contraction of the human isolated bladder to NKA was investigated by studying the affinities of eight structurally different receptor-selective antagonists (linear peptides, cyclic peptides and pseudopeptides, nonpeptide NK2 receptor antagonists). The affinities of the antagonists were compared to those measured for the same ligands at the NK2 receptors previously characterized in the rabbit pulmonary artery and hamster trachea. In the presence of a cocktail of peptidase inhibitors (bestatin captopril and thiorphan, 1 microM each) no significant correlation was found between pA2 values measured in the human bladder vs. those measured in the other two NK2 receptor-bearing preparation. In the presence of the aminopeptidase inhibitor amastatin, however, pA2 values of linear antagonists bearing an N-terminal Asp residue MEN 10,207 and MEN 10,376 were significantly enhanced and these pA2 values were used for analysis; a significant correlation was found between pA2 values measured in the human urinary bladder and rabbit pulmonary artery. The pseudopeptide analog of NKA (4-10), MDL 28,564 which also bears a N-terminal Asp residue behaved as an agonist and its action was enhanced by amastatin. We conclude that the NK2 receptor-mediating contraction of the human urinary bladder smooth muscle is similar to that previously characterized in the rabbit pulmonary artery (NK2A receptor category); in the human bladder smooth muscle an amastatin-sensitive peptidase (possibly aminopeptidase A) limits biological activity of linear peptide derivatives of NKA bearing a N-terminal Asp residue.
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PMID:Characterization of the tachykinin neurokinin-2 receptor in the human urinary bladder by means of selective receptor antagonists and peptidase inhibitors. 824 32

The saliva of the mosquito Aedes aegypti has previously been reported to contain a 1400-Da peptide with pharmacological properties typical of a tachykinin. In the present study this vasodilator has been purified to homogeneity and found to consist of two peptides: sialokinin I, with the sequence Asn-Thr-Gly-Asp-Lys-Phe-Tyr-Gly-Leu-Met-NH2, and sialokinin II, identical to sialokinin I except for an Asp in position 1. These peptides are present in amounts of 0.62 and 0.16 pmol (711 and 178 ng), respectively, per salivary gland pair. When assayed on the guinea pig ileum, both peptides are as active as the mammalian tachykinin substance P, with K0.5 values of 5.07, 6.58, and 4.94 nM for sialokinin I, sialokinin II, and substance P, respectively.
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PMID:Sialokinin I and II: vasodilatory tachykinins from the yellow fever mosquito Aedes aegypti. 827 54


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