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 homogenates of guinea pig lung, binding of 125I-Bolton-Hunter-labeled substance P (BHSP), Bolton-Hunter-labeled eledoisin (BHELE), and [125I]iodohistidyl neurokinin A (INKA) was investigated. Equilibrium dissociation constants (derived from "cold" saturation experiments) for BHSP, INKA, and BHELE were 0.96 +/- 0.15, 1.61 +/- 0.26, and 1.98 +/- 0.12 nM, respectively. Specific binding of all three radioligands was increased 2-3-fold by 10 microM phosphoramidon. The rank order of potency of unlabeled tachykinins in competing against BHSP was substance P (SP) greater than [Sar9,Met(O2)11]-SP greater than SP methyl ester greater than neuropeptide gamma greater than neurokinin A greater than or equal to neurokinin B = kassinin greater than or equal to eledoisin greater than or equal to scyliorhinin II much greater than neuropeptide K, indicating binding to sites with the general characteristics of NK1 receptors. Similar rank potency orders were observed for INKA and BHELE, showing binding to NK1 sites, rather than to NK2 or NK3 sites, which are labeled with high affinity by these radioligands in other tissues. For all radioligands, competition curves for SP and the NK1-selective agonist [Sar9,Met(O2)11]-SP could be resolved into two components, representing high and low affinity binding sites. These were present in the approximate ratios 2:3 (for BHSP), 1:1 (for INKA), and 8:1 (for BHELE). Other agonist competition curves also yielded high and low affinity components. The data suggest that BHSP and INKA bind partly and BHELE predominantly to high affinity NK1 receptors. The nature of the low affinity site(s) could be another tachykinin receptor or a low affinity state of the NK1 receptor. Binding to a "classical" NK2 receptor is unlikely, because selective NK2 receptor antagonists and analogs were very weak competitors. Our data suggest that, in addition to the NK1 receptor, another type of tachykinin receptor may exist in this tissue. The inability to detect NK2 binding sites is strikingly at variance with functional studies.
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PMID:Radioiodinated substance P, neurokinin A, and eledoisin bind predominantly in NK1 receptors in guinea pig lung. 137 Jul 5

Binding of [3H]substance P (SP) and histamine release were examined using a cloned mouse mast cell line. SP binding was saturable and specific. In the presence of 30 mM Na2SO4/50 mM Tris buffer, SP interacted with two types of binding sites with Kd values of 0.3 and 40 nM. High-affinity SP binding was blocked by the inclusion of 0.5 uM of the NK1 receptor selective ligand septide in the binding mixture. Neurokinin A (NKA) evoked concentration-dependent histamine release. At concentrations in the nanomolar range, the NK1 preferring agonists SP, SP methylester and physalaemin evoked less than or equal to 5% net release of histamine, which was substantially less than the maximum effect of NKA (+37%) in the micromolar range. Pretreatment of the cells with the NK2 antagonist peptide A reduced NKA-induced histamine release. [D-Arg1,D-Phe5,D-Trp7,9,Leu11]-substance P, a putative SP antagonist, also elicited histamine release in the micromolar range, apparently acting as an agonist at the NK2 site. Compound 48/80, N-terminal SP fragments, neurokinin B and the two selective NK2 receptor antagonists cyclo(Gln-Trp-Phe-(R)-[ANC-2]Leu-Met) (peptide A) and cyclo(Gln-Trp-Phe-Gly-Leu-Met) (peptide B) were ineffective. Although the results suggest the coexistence of functional NK1 and NK2 receptors, it appears that in this mast cell line neurokinin-induced histamine release is primarily mediated by the NK2 receptor, characterized biochemically as a low affinity binding site with a Kd value of 40 nM for SP.
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PMID:Evidence of NK1 and NK2 tachykinin receptors and their involvement in histamine release in a murine mast cell line. 137 67

A new non-peptide tachykinin antagonist, CP-96,345, inhibited airway plasma exudation induced in guinea-pigs by i.v. substance P in a dose-dependent manner with dose-ratios in the main bronchi of 5 at 1 nmol kg-1 and 19 at 100 nmol kg-1. At 100 nmol kg-1, CP-96,345 completely inhibited plasma exudation induced by either electrical stimulation of the cervical vagus nerves or i.v. capsaicin, indicating inhibition of the effects of endogenous tachykinins, but did not inhibit the bronchoconstrictor response to neurokinin A, suggesting selectivity for NK1 receptors. CP-96,345 may be useful in examining the role of endogenous tachykinins in vivo.
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PMID:Inhibition of neurogenic plasma exudation in guinea-pig airways by CP-96,345, a new non-peptide NK1 receptor antagonist. 137 95

Experiments were performed to examine the influence of interneuronal interactions on the expression of neurotransmitter receptors by developing mammalian CNS neurons. Receptors for the neuropeptide, substance P (SP), were assayed on embryonic rat motoneurons and other spinal cord neurons developing in vitro by the binding of 125I-SP to live neurons. Scatchard analysis showed the presence of high-affinity binding sites, and binding competition assays using SP, neurokinin A, or neurokinin B indicated that the high-affinity 125I-SP binding sites on these neurons were type NK1 tachykinin receptors, or SP receptors (SPRs). Neurons in the spinal cords of rats at Embryonic Day 14 displayed no SPRs. Cell-surface SPRs were detected on spinal cord neurons within 24 hr after they were placed in culture, however, and the level of 125I-SP binding increased for several days. SPRs were assayed on spinal motoneurons that had been identified by retrograde labeling with a fluorescent tracer, isolated in high purity by fluorescence-activated cell sorting (FACS), and maintained in culture. Motoneurons grown in isolation from other neurons developed SPRs in vitro along the same time course as neurons in heterogeneous spinal cord cultures. These results show that rat spinal motoneurons can express SPRs early in their development, and they suggest that the initial expression of SPRs by developing motoneurons does not require interaction with other neurons.
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PMID:Development of substance P receptors on rat motoneurons in vitro. 137 53

The pharmacological properties of 7,7-Diphenyl-2 [1-imino-2 (2-methoxy-phenyl)-ethyl] perhydroisoindol-4-one (3 aR, 7 aR) or RP67580 are described. This compound, derived from a novel chemical family, is a potent and selective substance P (SP) antagonist, in vitro and in vivo. In vitro, it inhibited in a competitive manner (IC50 = 10 nM) 3H-SP binding in rat brain (NK1 receptors). It did not interact with the two other tachykinin receptor sites (NK2 and NK3) nor the other receptor sites tested. Moreover, RP67580 competitively antagonized the contractile activity of SP on guinea-pig ileum (pA2 = 7.16); in contrast, it was inactive in rabbit pulmonary artery and in rat portal vein tissues which contain NK2 and NK3 receptors, respectively. In vivo, in the rat, RP67580 inhibited the plasmatic extravasation induced by administration of SP (ED50 = 0.04 mg/kg i.v.) as well as that induced by antidromic stimulation of a peripheral sensory nerve (ED50 = 0.15 mg/kg i.v.). In mice and rats, RP67580, like morphine, potently blocked the nociceptive effects of phenylbenzoquinone and formalin; its antinociceptive effect does not involve opiate receptors since it was not reversed by naloxone. These results indicate that RP67580 is a particularly valuable tool for investigating the physiological and pathological role of SP.
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PMID:[RP 67580, a potent and selective substance P non-peptide antagonist]. 137 87

We have measured the affinity of various analogs and fragments of the tachykinin substance P for the cloned rat NK1, NK2, and NK3 receptors heterologously expressed in Chinese hamster ovary cells. The hydrophobic carboxyl-terminal pentapeptide sequence substance P-(7-11) binds with similar affinity (2-20 microM) to all three receptors. Our data suggest that addition of one to three amino-terminal residues to this sequence results in the optimization of its interaction within the binding pocket of the NK1 receptor. The addition of Pro-Gln-Gln to the carboxyl-terminal pentapeptide sequence increases affinity for the NK1 receptor, either by providing additional binding interactions or by modifying the conformation of the carboxyl-terminal sequence. This latter hypothesis is supported by the observation that physalaemin and phyllomedusin, which also contain a proline residue in the position analogous to the proline residue 4 of substance P, are also selective for NK1 receptors. Tachykinins that lack this proline have no higher affinity for NK1 than [pGlu] substance P-(6-11). Conversely, addition of Pro-Gln-Gln to the carboxyl-terminal pentapeptide sequence is unfavorable for NK2 and NK3 receptor binding. Preliminary data suggest that tachykinins with high affinity (Kd less than 500 nM) for NK2 receptors contain an aspartate residue in the position analogous to residue 5 of substance P, suggesting that an ionic interaction with the receptor may contribute binding energy. Further experiments will be required to determine the structural determinants of the NK1, NK2, and NK3 receptors responsible for these binding properties.
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PMID:Determination of the amino acid residues in substance P conferring selectivity and specificity for the rat neurokinin receptors. 137 26

We have discovered a novel cyclopeptide substance P (SP) antagonist, FK 224 (N-[N2-[N-[N-[N-[2,3-didehydro-N-methyl-N-[N-[3-(2-pentylphenyl )- propionyl]-L-threonyl]tyrosyl-L-leucynyl]-D-phenylalanyl]-L-allo- threonyl]-L-asparaginyl]-L-serine-nu-lactone), which inhibited [3H]SP binding to guinea pig lung membranes in a dose-dependent manner. According to Rosenthal analysis, the inhibitory effect of FK 224 on [3H]SP binding appears to be competitive. In order to clarify the receptor subtype selectivity of FK 224, we have studied the interaction of FK 224 with three tachykinin receptors (NK1, NK2 and NK3) by using receptor binding techniques and in vitro bioassays, and have also compared FK 224 with the novel nonpeptide antagonist, (+/-)-CP-96,345. In binding experiments, FK 224 dose-dependently inhibited [3H]SP binding to rat cerebral cortical membranes (NK1) and [3H]neurokinin (NK) A (NKA) binding to rat duodenum smooth muscle membranes (NK2), but did not affect [3H]eledoisin binding to rat cerebral cortical membranes (NK3). In bioassay experiments, FK 224 inhibited SP-induced contraction of guinea pig ileum (NK1) and NKA-induced contraction of rat vas deferens (NK2) in a dose-dependent manner, but did not affect NKB-induced contraction of rat portal vein (NK3). In contrast, (+/-)-CP-96,345 inhibited SP-induced contraction of guinea pig ileum, but not NKA-induced contraction of rat vas deferens or NKB-induced contraction of rat portal vein. In the presence of FK 224, SP dose-response curves and NKA dose-response curves were shifted to the right in parallel with no depression of the maximal contraction.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:FK 224, a novel cyclopeptide substance P antagonist with NK1 and NK2 receptor selectivity. 137 96

FK224 (N-[N2-[N-[N-[N-[2,3-didehydro-N-methyl-N-[N-[3-(2- penthylphenyl)-propionyl]-L-threonyl]tyrosyl]-L-leucynyl]-D- phenylalanyl]-L-allo-threonyl]-L-asparaginyl]-L-serine-nu-lactone) is a novel neurokinin (NK) antagonist that exhibits selectivity for NK1 and NK2 receptors. The effects of FK224 on airway constriction and airway edema induced by NKs and nerve stimulation have been investigated in guinea pigs. FK224 inhibited the contraction of isolated guinea pig trachea induced by substance P (SP, 10(-8) M), NKA (10(-9) M) and NKB (10(-8) M) in a concentration-dependent manner, and the IC50 values were 2.6 x 10(-6), 1.3 x 10(-6) and 2.3 x 10(-7) M, respectively. Tracheal contraction induced by histamine and acetylcholine was not affected by FK224, suggesting a specific effect on NK-mediated responses. FK224 also inhibited the atropine-resistant contraction of isolated guinea pig bronchi induced by electrical field stimulation with an IC50 value of 3.5 x 10(-6) M. In in vivo experiments, FK224 given i.v. inhibited SP (13.5 micrograms kg-1)-, NKA (1.1 micrograms kg-1)- and capsaicin (3.1 micrograms kg-1)-induced airway constriction in guinea pigs with ED50 values of 0.39 mg kg-1, 0.36 mg kg-1 and 1.1 mg kg-1, respectively. FK224 also inhibited SP (1.3 micrograms kg-1)-, NKA (11 micrograms kg-1)- and capsaicin (100 micrograms kg-1)-induced airway edema with ED50 values of 0.14 mg kg-1, 0.29 mg kg-1 and 0.30 mg kg-1, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of FK224, a novel compound NK1 and NK2 receptor antagonist, on airway constriction and airway edema induced by neurokinins and sensory nerve stimulation in guinea pigs. 137 97

1. Release of the tachykinin, substance P, from the peripheral terminals of polymodal afferent C-fibres is thought to be largely responsible for the vasodilatation and plasma protein extravasation described as neurogenic inflammation. The effects of CP-96,345, a non-peptide antagonist at the substance P (NK1) receptor, on these vascular reactions were investigated in the rat. 2. Intravenously (i.v.) injected CP-96,345 (0.4-3.0 mumol kg-1) prevented the drop in blood pressure, a measure of the peripheral vasodilatation, evoked by substance P and neurokinin A in a dose- and time-dependent manner, but did not affect that elicited by the non-tachykinin peptides calcitonin gene-related peptide and vasoactive intestinal polypeptide. 3. Plasma protein extravasation evoked by i.a. infusion of substance P, antidromic stimulation of the saphenous or the vagus nerve, and stimulation of cutaneous afferent nerves with mustard oil, were each significantly inhibited by CP-96,345 (3.0-9.0 mumol kg-1, i.v.). Furthermore, CP-96,345 was orally active in blocking mustard oil-induced plasma extravasation with an ED50 of 10 mumol kg-1. 4. The inhibition of substance P-induced vasodilatation and of neurogenic plasma extravasation by CP-96,345 was stereospecific as the inactive isomer CP-96,344 (2R, 3R enantiomer of CP-96,345) had no effect. 5. Thus CP-96,345 is a specific, highly potent, long-acting and orally active inhibitor of tachykinin-mediated neurogenic inflammation.
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PMID:The non-peptide tachykinin antagonist, CP-96,345, is a potent inhibitor of neurogenic inflammation. 137 37

The activation of NK1 receptors on U373 MG human astrocytoma cells by substance P (SP) and related tachykinins was accompanied by an increase in taurine release and an accumulation of inositol phosphates. Both of these effects could be inhibited by spantide, a SP receptor antagonist. The relative potency of tachykinins in stimulating 3H-inositol phosphate accumulation correlated very well with their effects in stimulating the release of [3H]-taurine and inhibition 125I-Bolton-Hunter reagent-conjugated SP binding. The effect on [3H]taurine release was mimicked by a protein kinase C (PKC) activator, phorbol 12-myristate 13-acetate (PMA). The inactive phorbol ester analogue 4-alpha-phorbol 12,13-didecanoate, however, was without effect. Both SP- and PMA-induced releases of [3H]-taurine were markedly inhibited by staurosporine, a potent PKC inhibitor. Pretreatment of U373 MG cells with 10 microM PMA for 19 h to down-regulate PKC activity also markedly inhibited both SP- and PMA-induced releases of [3H]-taurine. Treatment of cells with 100 nM SP induced a time-dependent translocation of PKC from the cytosolic fraction to the membrane fraction. These findings are consistent with the hypothesis that an activation of NK1 receptors on U373 MG cells results in the release of inositol phosphates and activation of PKC, which in turn may regulate the release of taurine.
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PMID:Tachykinin-stimulated inositol phospholipid hydrolysis and taurine release from human astrocytoma cells. 137 85


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