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)

Five synthetic N-methylated analogs (II-V) of the C-terminal hexapeptide analog of substance P (SP), [pGlu6]SP6-11 (I) were evaluated for their metabolic stability and in vitro spasmogenic activity. The metabolic resistance of the analogs was tested by two SP degrading systems with different specificities, namely, the rat parotid and the hypothalamic slice systems. Their biological activity was assessed in the isolated guinea pig ileum. The analog [pGlu6, N-Me Phe7, N-Me Gly9]SP6-11 (III), had relative potency of 65% in the spasmogenic assay as compared to the parent compound. It was found to be more stable than the parent peptide in the hypothalamus, whereas in the parotid system it was susceptible as the parent peptide. However, the analog [pGlu6, N-Me Leu10]SP6-11 (II) (46% relative potency in the spasmogenic assay) was more stable than the parent peptide in the parotid system but did not show any improved stability in the hypothalamus. Identification of degradation products of the [pGlu6, N-Me Leu10]SP6-11 reflected the differences in the specificities of the two preparations. A significant drop in potency (7%) was observed for [pGlu, N-Me Phe7]SP6-11 (IV). This analog was more stable in the hypothalamic system than in the parotid. Introduction of a double methylation, [pGlu6, N-Me Leu10] SP6-11, contributed toward the stabilization in both degrading systems. Its relative spasmogenic activity was comparable to that of analog IV. In light of the above mentioned findings the implications of the N-methylated analogs with respect to putative CNS activity are discussed.
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PMID:Proteolytic resistance and biological activity of N-methylated analogs of [pGlu6] substance P6-11. 170 Dec 26

To determine the mechanism by which substance P (SP) activates human neutrophils, we examined the potencies of SP, the C-terminal peptides SP4-11 and SP6-11, and the N-terminal peptides SP1-9 and SP1-4 for inducing the increase in cytosolic free Ca2+ concentration ([Ca2+]i), superoxide (O2-) generation, and chemotaxis in human blood neutrophils. SP and the C-terminal peptides SP4-11 and SP6-11 and SP6-11 (10(-6)-10(-4) M) induced the increase in ([Ca2+]i, O2- generation, and chemotaxis of the neutrophils dose--dependently, whereas the N-terminal peptides SP1-9 and SP1-4 (up to 10(-4) M) were inactive in inducing these responses. Furthermore, the potencies of the two C-terminal peptides SP4-11 and SP6-11 were not parallel in these three responses. SP6-11 was 7.7-fold more potent in increasing [Ca2+]i than SP4-11, whereas SP4-11 was 16.6-fold more potent in inducing O2-generation than SP6-11. SP6-11 was also 2.1-fold more potent in inducing chemotaxis than SP4-11. Thus, we conclude that the C-terminal peptides of SP induce differential activations of human neutrophils.
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PMID:Differential effects of two C-terminal peptides of substance P on human neutrophils. 170 Dec 27

The effects of unilateral injections of two substance P fragments, the N-terminal substance P (1-7) (SP1-7) and the C-terminal substance P (6-11) (SP6-11) into the substantia nigra, pars reticulata on dopamine (DA) release in the ipsilateral striatum of halothane-anaesthetized rats were studied using microdialysis. SP1-7 and SP6-11 were also tested for their ability to modify the DA stimulation produced by intranigral injections of SP or neurokinin A (NKA). In addition, the SP antagonist Spantide I was tested for its ability to modify the DA stimulation produced by an intranigral injection of SP1-7. Intranigral injections of SP1-7 (0.001-5.0 nmol) inhibited DA release after low doses (0.001-0.01 nmol), but stimulated DA release after high doses (0.1-5.0 nmol). Striatal dihydroxyphenylacetic acid (DOPAC) levels increased moderately after high doses of SP1-7 (1.0-5.0 nmol). Intranigral injections of SP6-11 (0.01-5.0 nmol) inhibited DA release, but enhanced striatal DOPAC levels, dose-dependently. SP1-7 (0.01-0.1 nmol), but not SP6-11 (0.1 nmol), blocked the stimulation of striatal DA release produced by intranigral SP (0.07 nmol). Neither SP1-7 (0.1 nmol) nor SP6-11 (0.1 nmol) could modify the stimulation of striatal DA release produced by intranigral NKA (0.09 nmol). The increase in DA release after a high dose of SP1-7 (1.0 nmol) was not modified by co-administration with Spantide I (0.07 nmol).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Intranigral substance P modulation of striatal dopamine: interaction with N-terminal and C-terminal substance P fragments. 170 82

1. The effects of substance P and its fragments and analogue of a C-terminal fragment on cyclic AMP-dependent phosphorylation of synapsin I in synaptosomal membranes (SM) from cerebral cortex were investigated. 2. SP(I-II) and SP(1-4) at 10(-3) M caused a marked stimulation of synapsin I phosphorylation. 3. A C-terminal fragment of SP (SP6-11) had no effect on phosphorylation of synapsin 1. 4. Analogue of C-terminal fragment [(Tyr8)SP6-11] at 10(-3) M distinctly inhibits phosphorylation of synapsin I. 5. These data suggest that SPI-II and its C- and N-terminal fragments have a modulator function against the phosphorylation of some rat brain proteins.
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PMID:The influence of substance P and its fragments on endogenous phosphorylation of synaptosomal membrane protein (synapsin) from cerebral cortex of rat brain. 170 99

Evidence for the involvement of primary afferent nerves and their associated neuropeptides in in vivo immunologic responses has been based on experiments in rats in which destruction of primary afferent nerves by the sensory neurotoxin capsaicin results in a diminished ability of the animal to mount a primary antibody response to sheep red blood cell (SRBC) antigen. This effect was shown to be reversed by substance P infusion immediately following antigenic stimulation. In this report we show that neurokinin A (NKA) is 12 times more potent than substance P in its capacity to reverse the effects of neonatal capsaicin pretreatment on the antibody response. Neurokinin A has a pD2 of 6.65 compared to 5.98 for substance P. In addition, NKA was more potent than substance P in reversing the effects of surgical lesions 2 days prior to antigenic stimulation. The effects of the D- and L-Pro9 analogues of [Glp6, Pro9]-SP6-11 on the plaque-forming cell response in capsaicin-treated rats provide further support for the hypothesis that the tachykinin receptor modulating the primary antibody response is an NK-2 receptor. These results demonstrate, for the first time, a role for NKA in in vivo immunomodulation.
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PMID:Tachykinin-mediated modulation of the primary antibody response in rats: evidence for mediation by an NK-2 receptor. 170 44

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

The tachykinins substance P (SP) and neurokinin A are believed to be major mediators of neurogenic inflammation. To determine whether the skin reactivity to tachykinins is increased in asthmatics, we examined the erythemas and wheals induced by intradermal injections of SP, the C-terminal peptide SP6-11, the N-terminal peptide SP1-9 and neurokinin A (10(-7)-10(-5) M) in 10 allergic asthmatics and 9 normal subjects. SP and SP1-9 induced both erythemas and wheals in a concentration-dependent manner in allergic asthmatics and in normal subjects, whereas SP6-11 and neurokinin A induced only wheals in both groups. SP induced greater erythemas and wheals in allergic asthmatics than in normal subjects. However, the wheals induced by neurokinin A were not significantly different between the two groups. SP1-9 also induced greater erythemas and wheals in allergic asthmatics than in normal subjects, whereas the wheals induced by SP6-11 were not significantly different between the two groups. Therefore, the increased skin reactivity to SP was dependent on the N-terminal peptide but not on the C-terminal peptide. We conclude that the skin reactivity to SP but not to neurokinin A is increased in allergic asthmatics.
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PMID:Skin reactivity to substance P, not to neurokinin A, is increased in allergic asthmatics. 171

The analogues [Glu(OBzl)11]SP6-11 and [Glu(OBzl)11]SP5-11 of the C-terminal hexapeptide and heptapeptide of Substance P have been synthesized by conventional solution methods. In each analogue the SCH3 group of Met11 is replaced by the COOCH2C6H5 group. The in vitro activity of both analogues has been determined on three biological preparations: guinea pig ileum (GPI), rat vas deferens (RVD), and rat portal vein (RPV). The selectivity for the different receptors has been studied by utilizing atropine-treated guinea pig ileum (GPI + At). The results showed that both analogues are mainly active on GPI through the NK-1 receptor and that both analogues are equipotent to Substance P.
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PMID:Synthesis and biological activity of substance P C-terminal hexapeptide and heptapeptide analogues. 171 23

The isosteric methyleneoxy psi (CH2O) function was employed as a novel peptide-bond surrogate and incorporated into sequences of two neuropeptides, substance P (SP) and enkephalin. A pseudopeptide analogue [pGlu6,Phe8 psi(CH2O)Gly9]SP6-11 (7) of SP related C-terminal hexapeptide [pGlu6]SP6-11 and two pseudopeptide analogues of [Leu5]enkephalinamide, [Tyr1 psi (CH2O)Gly2, Leu5] enkephalinamide (11) and [Gly2 psi (CH2O)-Gly3, Leu5]enkephalinamide (17), were synthesized. The N alpha-protected pseudodipeptidic units were incorporated in the appropriate peptide sequences by using conventional coupling methods in solution. Compound 7 was a potent agonist (EC50 = 4.8 nM) of substance P as compared to the parent peptide [pGlu6]SP6-11 (EC50 = 1.2 nM), in stimulating contraction of the isolated guinea pig ileum (GPI). Analogue 7 was more potent on the neuronal (NK-3) than on the muscular (NK-1) tachykinin receptors in the GPI as shown by the ratio of activities, EC50 (NK-1)/EC50 (NK-3) = 3.16, thus displaying an improved selectivity for the NK-3 tachykinin receptor subtype as compared to that of [pGlu6]SP6-11, EC50 (NK-1)/EC50 (NK-3) = 0.44. In the rat vas deferens (RVD) assay, a typical NK-2 system, the pseudopeptide analogue 7 was (EC50 = 2 microM) 10-fold more potent than the parent peptide and 20-fold less potent than eledoisin, an NK-2 selective tachykinin. The pseudopeptide enkephalin analogue 17 had low biological activity when tested in the electrically induced GPI (EC50 = 2.3 microM) and was inactive in the mouse vas deferens (MVD) assay. In the rat brain membrane (RBM) binding assay analogue 17 had low affinity (in the micromolar range) for both the mu and delta binding sites. In contrast, analogue 11 was a potent enkephalin agonist (EC50 = 30 nM), being equipotent to [D-Ala2, Leu5]enkephalinamide (DALE) in the GPI assay. In the MVD, analogue 11 showed a substantially reduced activity (EC50 = 92 nM), being about 10-fold less potent than DALE. In the RBM binding assay analogue 11 showed high affinity (in the nanomolar range) for both mu and delta binding sites with increased selectivity for the delta sites as shown by the ratio of the apparent affinities for both receptors, Ki (delta)/Ki (mu) = 2.1. The contribution of the modified peptide bonds in the mode of interaction of SP and enkephalin at their corresponding receptors is discussed.
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PMID:Pseudopeptide analogues of substance P and leucine enkephalinamide containing the psi (CH2O) modification: synthesis and biological activity. 171 57

1. We have used synaptosomal membranes to study the influence of substance P and its fragments and analogues of its C-terminal fragment on Ca2+/calmodulin-dependent synapsin I endogenous phosphorylation. 2. SP1-11, SP1-4, [Tyr8]SP6-11 and [pGlu6, Tyr8]SP6-11 at 10(-3) M greatly inhibited synapsin I phosphorylation. 3. SP6-11 at all investigated concentrations and SP1-11, SP1-4, [Tyr8]SP6-11, [pGlu6, Tyr8]SP6-11 at 10(-4) and 10(-5) M were ineffective. 4. The results indicate that SP1-11 and its N-terminal fragment and analogues of its C-terminal fragment act on the phosphorylation of specific synaptic protein (synapsin I) and therefore may influence the release of neurotransmitters, membrane conductance and potentiation or inhibition of other signalling systems.
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PMID:Substance P and its fragments affect Ca2+/calmodulin-dependent synaptosomal membrane protein phosphorylation from rat cerebral cortex. 172 84


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