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)

As an extension of our studies on discovering a novel substance P (SP) antagonist, we modified the previously reported dipeptide, N2-[N2-(1H-indol-3-ylcarbonyl)-L-lysyl]-N-methyl-N-(phenyl-methyl) -L- phenylalaninamide (2b). The lysine part in 2b was first optimized to a (2S,4R)-hydroxyproline derivative (3h), which is 2-fold more potent than 2b in [3H]SP binding assay using guinea pig lung membranes. Next we modified the 1H-indol-3-ylcarbonyl part in 3h. Introduction of a methyl group at the indole nitrogen enhanced the oral activity, while retaining the binding activity. Finally, we modified the phenylalanine part to culminate in the most potent compound 7k (FK888), which is a potent SP antagonist with NK1 selectivity as well as oral activity.
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PMID:Studies on neurokinin antagonists. 4. Synthesis and structure-activity relationships of novel dipeptide substance P antagonists: N2-[(4R)-4-hydroxy-1-[(1-methyl-1H-indol-3-yl)carbonyl]-L-prolyl]-N- methyl-N-(phenylmethyl)-3-(2-naphthyl)-L-alaninamide and its related compounds. 751 2

Nitric oxide synthase-containing cells were visualized in the anterior pituitary gland by immunocytochemistry. Consequently, we began an evaluation of the possible role of NO in the control of anterior pituitary function. Prolactin is normally under inhibitory hypothalamic control, and in vitro the gland secretes large quantities of the hormone. When hemipituitaries were incubated for 30 min in the presence of sodium nitroprusside, a releaser of NO, prolactin release was inhibited. This suppression was completely blocked by the scavenger of NO, hemoglobin. Analogs of arginine, such as NG-monomethyl-L-arginine (NMMA, where NG is the terminal guanidino nitrogen) and nitroarginine methyl ester, inhibit NO synthase. Incubation of hemipituitaries with either of these compounds significantly increased prolactin release. Since in other tissues most of the actions of NO are mediated by activation of soluble guanylate cyclase with the formation of cyclic GMP, we evaluated the effects of cyclic GMP on prolactin release. Cyclic GMP (10 mM) produced an approximately 40% reduction in prolactin release. Prolactin release in vivo and in vitro can be stimulated by several peptides, which include vasoactive intestinal polypeptide and substance P. Consequently, we evaluated the possible role of NO in these stimulations by incubating the glands in the presence of either of these peptides alone or in combination with NMMA. In the case of vasoactive intestinal polypeptide, the significant stimulation of prolactin release was augmented by NMMA to give an additive effect. In the case of substance P, there was a smaller but significant release of prolactin that was not significantly augmented by NMMA. We conclude that NO has little effect on the stimulatory action of these two peptides on prolactin release. Dopamine (0.1 microM), an inhibitor of prolactin release, reduced prolactin release, and this inhibitory action was significantly blocked by either hemoglobin (20 micrograms/ml) or NMMA and was completely blocked by 1 mM nitroarginine methyl ester. Atrial natriuretic factor at 1 microM also reduced prolactin release, and its action was completely blocked by NMMA. In contrast to these results with prolactin, luteinizing hormone (LH) was measured in the same medium in which the effect of nitroprusside was tested on prolactin release, there was no effect of nitroprusside, hemoglobin, or the combination of nitroprusside and hemoglobin on luteinizing hormone release. Therefore, in contrast to its inhibitory action on prolactin release NO had no effect on luteinizing hormone release. Immunocytochemical studies by others have shown that NO synthase is present in the folliculostellate cells and also the gonadotrophs of the pituitary gland. We conclude that NO produced by either of these cell types may diffuse to the lactotropes, where it can inhibit prolactin release. NO appears to play little role in the prolactin-releasing action of vasoactive intestinal polypeptide and substance P, but mediates the prolactin-inhibiting activity of dopamine and atrial natriuretic factor.
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PMID:Role of nitric oxide in control of prolactin release by the adenohypophysis. 752 11

In order to investigate whether the oxidant airborne pollutant nitrogen dioxide (NO2) affects airway smooth muscle responsiveness, the contractile response of guinea pig main bronchi after in vitro exposure to 2.5 ppm of nitrogen dioxide was studied. Main bronchi were cannulated and exposed for 2 or 4 h to a constant flow of either NO2 or air. After exposure, bronchial rings were obtained and placed in a 37 degrees C jacketed organ bath filled with Krebs-Henseleit solution. Concentration-response curves were performed for acetylcholine (10(-9)-10(-3) M), substance P (10(-9)-10(-4) M), and neurokinin A (10(-10)-10(-5) M), and voltage-response curves (12-28 V) were performed for electrical field stimulation. There was no significant difference in either the smooth muscle maximal contractile response, or sensitivity between the bronchi exposed to NO2 and those exposed to air. We conclude that in vitro exposure to 2.5 ppm of NO2 does not alter airway smooth muscle responsiveness in guinea pigs.
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PMID:In-vitro exposure of guinea pig main bronchi to 2.5 ppm of nitrogen dioxide does not alter airway smooth muscle response. 754 87

Published data for substance P (SP) content of sciatic nerves in control rats vary greatly. This study sought possible reasons for this variability by examining the influence of homogenisation procedures, freezing and selection of left/right nerve or proximal/distal segments. Substance P-like immunoreactivity (SP-LI) content (pg/mg nerve protein +/- SD) was significantly greater in sciatic nerves which had been homogenised using motor-powered equipment (615.4 +/- 146.3) as opposed to a hand-held pestle (445.4 +/- 111.8). Our second investigation revealed that freshly homogenised nerve tissue yielded greater SP-LI (508.8 +/- 88.7) than either tissue snap frozen in liquid nitrogen (307.6 +/- 77.9), snap-frozen and stored at -70 degrees C for 7 days (331.8 +/- 53.5), or tissue allowed to remain in the cadaver for 1 h and subsequently dissected and homogenised immediately (412.6 +/- 105.8). These data also show that storage at -70 degrees C imposes no further losses on those caused by freezing and extraction of frozen tissue. Two further studies indicated no variation between left and right sciatic nerves nor any proximal-distal gradients. Hence, this study illuminated the need for samples to be homogenised using motor-powered equipment immediately upon dissection, followed by SP extraction, for complete avoidance of losses of SP-LI.
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PMID:The extraction and assay of substance P in the rat sciatic nerve. 768 97

We report on the synthesis and the pharmacological properties of a new series of tachykinin antagonists based on the pseudopeptide pharmacophore cyclo[-Abo-Asp(D-Trp-Phe-N(Me)Bzl)-] which contains the 2-azabicyclo[2.2.2]octane-3(S)-carboxylic acid (Abo) residue. Variation of the substituents on the tryptophan indole nitrogen was shown to modulate water solubility and transport properties of the analogs as well as potency in classical in vitro response and binding assays. One water-soluble compound, 16, in which the substituent was 3-carbonylpropionate, strongly prolonged the reaction time in the mouse hot-plate test both after iv or oral administration and was devoid of degranulating activity in rat peritoneal mast cells.
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PMID:Tetrapeptide tachykinin antagonists: synthesis and modulation of the physicochemical and pharmacological properties of a new series of partially cyclic analogs. 838 71

We have investigated the effects of neonatal capsaicin treatment of rabbits on the development of bronchial hyperresponsiveness following allergen exposure from birth. In vivo airways responsiveness was assessed as the concentrations of histamine to cause a 35% decrease in compliance (PC35) and a 50% increase in resistance (PC50). Rabbits treated with vehicle capsaicin (10% ethanol, 10% tween 80 and 80% saline) and then immunised with Altenaria tenius (40,000 protein nitrogen units (PNU)/ml + AL(OH)3 + saline in a ratio 2:1:1) were more responsive to aerosol histamine in vivo at three months of age when compared to sham-immunised (AL(OH)3 + saline 1:3) or saline-treated rabbits for compliance measurements (P < 0.05). However, immunised rabbits although not significantly different to sham-immunised (P > 0.05) were significantly more responsive than saline-treated rabbits for resistance measurements (P < 0.05). Neonatal capsaicin treatment significantly attenuated the increased responsiveness seen in immunised rabbits for both compliance and resistance measurements (P < 0.05). The bronchial hyperresponsiveness is unlikely to be due to cellular infiltration per se as cell numbers assessed by bronchoalveolar lavage were not significantly different between groups (P > 0.05). Exogenous in vitro functional bronchial responses to capsaicin were increased in vehicle-immunised rabbits, an effect attenuated by neonatal capsaicin treatment (P < 0.05) whereas responses to methacholine, histamine or electrical field stimulation remained similar between groups (P > 0.05). Bronchial levels of calcitonin gene-related peptide- and substance P-like immunoreactivity were unaffected by any treatment (P > 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The effect of neonatal capsaicin on the development of bronchial hyperresponsiveness in allergic rabbits. 845 97

We report on the synthesis and the pharmacological properties of a new series of tachykinin antagonists based on the tripeptide Ac-Thr-D-Trp(CHO)-Phe-N(Me)-Bzl (1, FR113680) partly modified on the C-terminal amide part. Stereochemistry around the benzilic carbon, as well as nitrogen substitution was investigated. Selected compounds were tested on guinea pig ileum for NK-1, rat colon and rat portal vein for NK-2 and NK-3 receptors, respectively. Two of these peptides were shown to have higher tachykinin antagonist activity (pA2 > 8.8) and selectivity for NK-1 receptors compared with compound 1 taken as reference (Table 2). In addition we investigated the stability of compounds 2 and 3 on guinea pig plasma and liver homogenate.
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PMID:Synthesis and in vitro activities of highly potent and selective tripeptide antagonists of the neurokinin NK-1 receptor. 859 72

Chronic exposure of rats to high concentrations of SO2 gas induces a syndrome similar to human chronic bronchitis. The aim of these studies was to determine if substance P (SP) content in the trachea or lungs was elevated in this animal model of chronic bronchitis, and whether an increase in SP content was associated with an increase in preprotachykinin gene-I (PPT) mRNA expression. Rats were exposed to air (controls) or 250 ppm SO2 gas, 5 h per day, 5 days per week, for a period of 4 wk. Animals were killed and the lungs and trachea were frozen in liquid nitrogen for measurement of SP content by enzyme-linked immunosorbent assay. The SP content of the tracheas from SO2-exposed rats was 3-fold greater than controls (8.9 +/- 1.2 and 3.0 +/- 0.7 pmol/g tissue, respectively; P=0.0005), whereas the SP content of the lungs was not different (SO2 = 4.8 +/- 0.8 and air = 3.0 +/- 0.7 pmol/g tissue, respectively; P = 0.06). In order to determine whether SP synthesis in the cell bodies of the C-fibers innervating the trachea and lungs accompanied a change in SP levels, thoracic dorsal root ganglia and nodose ganglia were removed and PPT mRNA quantitated by Northern analysis. There was no difference in PPT mRNA between control and SO2-exposed rats in nodose or dorsal root ganglia. These results suggest a post-transcriptional mechanism of PPT regulation. Elevated SP levels could play a protective role in the responses of the airways to chronic exposure of inhaled irritants.
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PMID:Substance P content and preprotachykinin gene-I mRNA expression in a rat model of chronic bronchitis. 860 Sep 37

The mammalian respiratory tract is densely innervated by sensory and autonomic fibres. Subsets of the nerves contain bioactive regulatory peptides, such as substance P, calcitonin gene-related peptide (CGRP), and neurokinins. The sensory nervous system responds to inhaled irritants, resulting in a release of neuropeptides and, thus, a decrease in the peptide immunoreactivity of the fibres. We examined the effects of inhaled nitrogen dioxide (NO2), a well-known indoor and outdoor air pollutant, on pulmonary sensory neuropeptides. Guinea-pigs were exposed for 4 h to 18 parts per million (ppm) NO2 or to air (n = 5 each). At the end of the exposure, they were killed with urethane and their lungs were fixed in 1% paraformaldehyde in phosphate-buffered saline. Cryostat sections were stained with antisera to an anatomical nerve marker, protein gene product (PGP) 9.5, and to CGRP and tachykinins, utilizing the avidin-biotinylated peroxidase method. In the noncartilaginous airways (diameter < 250 microns) of NO2-exposed animals, less tachykinin- and CGRP-immunoreactive nerve fibres were found compared with controls. No change was seen in the total nerve fibre distribution (PGP 9.5). It is concluded that the peptidergic nerves of guinea-pig peripheral airways are a sensitive indicator of exposure to nitrogen dioxide.
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PMID:In vivo exposure to nitrogen dioxide (NO2) induces a decrease in calcitonin gene-related peptide (CGRP) and tachykinin immunoreactivity in guinea-pig peripheral airways. 888 Jan 1

The influence of long-term hypoxia on substance P (SP) and neuropeptide Y (NPY)-like immunoreactivity (LI) in discrete brain areas and peripheral structures was assessed by radioimmunoassay. Rats were exposed to normobaric hypoxia (10% O2 in nitrogen) for 14 days. In the carotid bodies of hypoxic animals, NPY-LI was significantly increased (56% vs. normoxic controls) while SP-LI was unchanged. In the brain, NPY-LI was increased in the ventrolateral medulla oblongata (23%) and in the striatum (53%); however, SP-LI was unaltered in these two regions. In the anterior pituitary, NPY-LI was increased (99%), while SP-LI was decreased (37%). No significant alteration in NPY-LI and SP-LI was observed in other discrete brain areas or peripheral structures studied. These results show that, in the rat, long-term hypoxia induces changes in NPY-LI or SP-LI in a few central and peripheral structures; these biochemical alterations may be linked to adaptative mechanisms involving morphological changes in carotid bodies or alterations in sympathetic control and neuroendocrine function.
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PMID:Alteration in central and peripheral substance P- and neuropeptide Y-like immunoreactivity after chronic hypoxia in the rat. 889 Dec 49


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