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)

In light of current interest in substance P as a bronchoconstrictor, several pharmacologic antagonists of known mediators of anaphylaxis were tested for possible activity against this neuropeptide. Concentration-dependent contractions of the isolated guinea-pig tracheal strips to substance P (10(-8) to 10(-5) M) were elicited. These contractions were inhibited by substance P receptor antagonists, D-Arg1-D-Trp7,9-Leu11 and D-Pro2-D-Trp7,9-substance P (10(-6) to 10(-4) M). Substance P-induced contractions were not inhibited by histamine, alpha and beta adrenergic receptor antagonists or by cyclooxygenase inhibition. However, atropine enhanced contractions to substance P. Both vasoactive intestinal polypeptide (10(-7), 10(-6) and 10(-4) M) and isoproterenol (10(-7) M) were able to reverse an ongoing substance P (10(-5) M)-induced contraction. Also, at a concentration of 10(-5) M, substance P increased cyclic GMP accumulation, but had no effect on the concentration of cyclic AMP. A 15-min pretreatment with either verapamil or nifedipine (10(-8) M) had no effect on substance P-induced contractions, whereas the purported intracellular Ca++ antagonist, 8-[N,N-diethylamino]-octyl 3,4,5-trimethoxybenzoate hydrochloride (10(-4) M) produced a rightward shift of a substance P concentration-response curve. A selective calmodulin inhibitor, N-(6-aminohexyl)-5-chloro-1-naphthalene-sulfonamide (10(-4) M) failed to affect the contraction produced by 10(-5) M substance P. When guinea-pig tracheal strips were washed and allowed to re-equilibrate in 0 Ca++ buffer, the initial maximum contractions to substance P (10(-5) M) were equal for both regular (1.8 mM) Ca++ and 0 Ca++ buffer.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of substance P-induced contractions of guinea-pig trachea. 242 83

We have prepared a fluorescent conjugate of porcine calmodulin with 5-(dimethylamino)-1-naphthalene-sulfonyl chloride that is highly sensitive to both calcium binding and protein binding. We have used the fluorescence of this conjugate in addition to the intrinsic peptide fluorescence to show that adrenocorticotropic hormone (ACTH), beta-endorphin, glucagon, and substance P undergo calcium-dependent binding by calmodulin, with competition for common binding sites. The dissociation constants determined in the presence of 0.85 mM CaCl2 and 0.2 N KC1, pH 7.3 at 25 degrees C, range from 1.5 muM to 3.4 muM. The alpha-melanocyte-stimulating hormone, bombesin, and somatostatin also bind, with dissociation constants between 60 muM and 90 muM. Angiotensins I and III, bradykinin, neurotensin, physalaemin, substance P octapeptide, insulin, and Leu- and Met-enkephalin show little or no binding. Sequence comparisons show that the peptides that bind calmodulin well contain regions structurally similar to the recognition sequence for the cAMP-dependent protein kinase and to the sequences surrounding phosphorylated serine residues in several calmodulin binding proteins. This result suggests that modification of calmodulin binding sites in calmodulin-dependent proteins is one of the functions of protein kinase. Calcium has a dual role in peptide binding by calmodulin. The occupation of calcium binding sites having a pK approximately 4 results in a 2-fold increase in peptide binding affinity.
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PMID:Binding of simple peptides, hormones, and neurotransmitters by calmodulin. 618 Jul 61

The present study was aimed to determine the effect of calmodulin inhibitors on the relaxant response of isolated dog and monkey cerebral arteries to vasodilator nerve stimulation, which is hypothesized to be mediated by nitric oxide (NO) from nerve endings. The relaxations caused by nerve stimulation by electrical pulses in endothelium-denuded arteries were attenuated by treatment with calmidazolium and W-7 (N-(6-aminohexyl)-5-chloro-1-naphthalene sulfonamide hydrochloride) and were abolished by NG-nitro-L-arginine, an inhibitor of nitric oxide synthase, and tetrodotoxin. The calmodulin inhibitors also attenuated the relaxations caused by nicotine and substance P, which were endothelium-independent and -dependent, respectively, but did not influence the relaxant response to NO. It is concluded that calmodulin is required for activation of the NO synthase present in the vasodilator nerve as well as that in the endothelium.
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PMID:Inhibition by calmodulin antagonists of the neurogenic relaxation in cerebral arteries. 751 92

In the course of a program aimed at synthesizing novel, potent NK-1 tachykinin receptor antagonists, we developed upon a bioactive model by comparing the low energy structures of a series of peptide and nonpeptide Substance P antagonists. The comparison was based on the superimposition of the aromatic rings, assuming that the rest of the molecule behaves predominantly as a template to arrange the key aromatic groups in the right spatial position. A series of 2-aminocyclohexane carboxylic acid analogues were then selected as the best templates for reproducing the postulated bioactive structure, leading to several pseudo-peptides with interesting biological activity. According to the molecular modeling, these compounds exhibit a neat parallel facing of the indolyl and naphthyl groups at about 3 A distance. Ultraviolet absorption and steady state fluorescence measurements support this conclusion, showing a linear correlation between the spectral properties and the binding affinity of these analogues. Stacking of the indole ring with naphthalene gives rise to a complex characterized by a well-defined molar extinction coefficient. Consistently, steady state and lifetime fluorescence measurements suggest that the quenching process is ascribable to ground-state interactions between the chromophores. Implications of the pi stacking propensity of aromatic groups in the biological activity of the compounds examined are briefly discussed.
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PMID:Synthesis and biological evaluation of novel NK-1 tachykinin receptor antagonists: the use of cycloalkyl amino acids as a template. 757 45

A spectroscopic investigation, based on both electronic absorption and emission spectra as well as on chiroptical data, was performed on novel neurokinin 1 (NK1) tachykinin receptor antagonists, exhibiting interesting biological activity. These pseudopeptides have two fluorophores, i.e. indole (I) and naphthalene (N), and a central scaffold with different conformational mobility. Absorption spectra in methanol show the presence of a new band with respect to the sum spectrum of the isolated chromophores at around 285 nm, the intensity of which linearly increases as the bioactivity increases. This absorption disappears by using dioxane as solvent. It is ascribed to an intramolecular I-N charge-transfer (CT) complex that forms to different extent, depending on the flexibility of the scaffold. Under this condition, the molecules fold and apparently attain the correct conformation for competing substance P binding to the NK1 receptor, lending plausibility to the role of dipolar charged, spatially close aromatic moieties as topochemical elements in the mechanism of action of substance P antagonists. The excited-behavior parallels that in the ground state, as the quenching of the singlet state at 340 nm is found to be linearly dependent on the biological activity, too. Upon decreasing solvent polarity (methanol vs dioxane) the emissions of the dipolar state at around 370 nm disappears, while exciplex emission in the range of 400-500 nm occurs. This transition from charge-separated to exciplex-like states by lowering the dielectric constant of the medium very likely reflects a change in the structural features of the intramolecular I-N stacked complex, from a twisted or an asymmetrically overlapped conformation of the indolyl and naphthyl rings to a face-to-face geometry. Implications of the rigidity of the molecules, arising from the formation of the intramolecular CT complex, on the ellipticity are briefly discussed.
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PMID:Absorption, emission, and chiroptical spectra of neurokinin 1 tachykinin receptor antagonists: the role of charge-transfer states on the biological activity. 906 74

A method for the detection of substance P and its metabolites using capillary electrophoresis with post-capillary derivatization and laser-induced fluorescence detection is described. The post-capillary chemical derivatization system employs naphthalene-2,3-dicarboxaldehyde and beta-mercaptoethanol. Two reactor designs were evaluated for the determination of substance P and its metabolites. The fluorescent spectroscopic properties of the derivatives under optimal separation conditions were also examined. The final system was evaluated for the investigation of substance P metabolism in brain following perfusion of the striatum with substance P using microdialysis sampling.
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PMID:Evaluation of capillary electrophoresis with post-column derivatization and laser-induced fluorescence detection for the determination of substance P and its metabolites. 927 Nov 26

A series of pseudopeptides, containing two fluorophores, such as naphthalene (N) and indole (I), and exhibiting interesting biological activity as tachykinin receptor antagonists, were investigated by electronic absorption, CD and steady-state fluorescence experiments. In polar solvents (e.g. methanol), bioactivity is coupled with a stacked, charge-separated complex between I and N, the amount of which depends on the stereochemical features and conformational mobility of the central scaffold in the molecules examined. This agrees with the idea that dipolar charged, spatially close, aromatic moieties are important topochemical elements in the mechanism of action of these receptor antagonists. Molecular mechanics calculations allowed us to build up hypothetical, low-energy conformations of a few representative pseudopeptides, whose structural features are consistent with the experimental findings.
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PMID:A spectroscopic and molecular modeling study on novel pseudopeptides exhibiting biological activity. 1053 41

This paper describes the development of analytical methodology for the separation of naphthalene-2,3-dicarboxaldehyde (NDA)-derivatized substance P (CBI-SP) and five lysine-containing metabolites by micellar electrokinetic chromatography (MEKC). The effect of surfactant composition and organic modifiers on the separation was investigated. The final separation buffer consisted of 80 mM sodium cholate in 50 mM N-tris (hydroxymethyl)methyl-2-aminoethanesulfonic acid (TES), pH 7. All six lysine-containing peptides were separated under these conditions.
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PMID:Separation of naphthalene-2,3-dicarboxaldehyde-derivatized-substance P and its metabolites by micellar electrokinetic chromatography. 1087 58

Glycine release was facilitated by the activation of presynaptic ATP receptors (P(2X)-type) in a preparation of dissociated trigeminal nucleus pars caudalis neurons in which the native synaptic boutons were preserved. The action of ATP was completely blocked by substance P (SP) without alteration of the miniature IPSC (mIPSC) amplitude distribution. SP itself had no effect on mIPSC frequency or amplitude. The inhibitory effect of SP on ATP action was blocked by CP99994, indicating that the SP receptors are of the neurokinin-1 type. The ATP-induced facilitation of the mIPSC frequency was unaffected by Cd(2+). Moreover, SP did not inhibit the increase in mIPSC frequency induced high K(+) application, suggesting that SP did not modulate voltage-dependent calcium channels or subsequent steps in the release process. KT5720 and phorbol 12-myristate 13-acetate did not block SP action, indicating that neither the cAMP-protein kinase A nor the protein kinase C pathway mediates the SP effects. However, in the presence of N-(6-aminohexyl)-5-chloro-1-naphthalene sulphonamide (W-7), SP was no longer able to inhibit the ATP-induced stimulation of mIPSC frequency. 1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-l-tyrosyl]-4-phenylpiperazine also suppressed the SP action, suggesting that SP modulates P(2X) receptors via a Ca(2+)/calmodulin-dependent protein kinase II-mediated pathway. In conventional whole-cell mode, the presence of W-7 in the patch pipette did not affect the SP inhibitory action. Thus, SP is not likely to be generating its modulation through the production of a retrograde signal (involving calmodulin) from the postsynaptic cell to the presynaptic boutons. These results are the first demonstration of the modulation of one presynaptic receptor by another. Because SP inhibits the ATP stimulation of glycine release, SP may play a significant role in hyperalgesia or chronic pain.
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PMID:Substance P abolishes the facilitatory effect of ATP on spontaneous glycine release in neurons of the trigeminal nucleus pars caudalis. 1131 82

The metabolism of substance P (SP) was investigated in rat striatum using in vivo microdialysis. Substance P was perfused for 5 h at 0.2 microl/min, and its metabolism was followed for over 13 h. The resulting samples were derivatized precolumn with naphthalene-2,3-dicarboxaldehyde (NDA)/cyanide, separated and detected by cyclodextrin-modified electrokinetic chromatography with laser-induced fluorescence detection (CDMEKC-LIF). Substance P rapidly degraded to form the fragments (3-11), (1-9), (1-4) and, to a lesser extent, (1-7). The metabolites reached steady-state levels 2-3 h after addition of SP.
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PMID:Investigation of the metabolism of substance P in rat striatum by microdialysis sampling and capillary electrophoresis with laser-induced fluorescence detection. 1148 96


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