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)

Concentrations of phenoxybenzamine ranging from 0.33-33 micron produced a competitive block of kassinin-, neurokinin A- and neurokinin B-induced contractions of the guinea-pig ileum with pA2 values of 6.6, 5.6 and 6.2, respectively. Physalaemin- and substance P-induced contractions were insensitive to phenoxybenzamine treatment. Differences in sensitivity to phenoxybenzamine and pA2 values suggest the existence of at least two and possibly three neurokinin receptors in the guinea-pig ileum. Injected intrathecally to mice, phenoxybenzamine blocked neurokinin-induced, but not bombesin- or somatostatin-induced, reciprocal hind limb scratching. Phenozybenzamine was 6-32 times more effective in blocking neurokinin B-induced scratching than substance P, kassinin, physalaemin or neurokinin A-induced scratching. These results suggest that multiple peripheral and central neurokinin receptors can be differentiated from one another by phenoxybenzamine treatment. They also suggest the existence of a distinct neurokinin B receptor in the mouse spinal cord and the apparent identification of a third neurokinin receptor in the guinea-pig ileum.
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PMID:A differentiation between peripheral and central neurokinin receptors using phenoxybenzamine. 287 38

A series of analogues of the partial sequence NKB-(4-10) (H-Asp-Phe-Phe-Val-Gly-Leu-Met.NH2) was prepared in an attempt to identify selective agonists for the neurokinin B receptor type. The compounds were tested in the dog carotid artery, the rabbit pulmonary artery and the rat portal vein to evaluate their affinity for the receptors of substance P, neurokinin A and neurokinin B respectively. It has been shown that the replacement of Val7 with MePhe increased significantly the affinity of NKB-(4-10) for the neurokinin B receptor and confered marked selectivity. [MePhe7]NKB-(4-10) was practically inactive as stimulant of the receptor for NKA and was a weak agonist on the receptor for SP. Such significant changes in the pharmacological spectrum of [MePhe7]NKB-(4-10) cannot be attributed to protection from metabolism and appear to be due to changes in the peptide conformation.
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PMID:Specific agonists for neurokinin B receptors. 303 72

LY303870 [(R)-1-[N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4- (piperidin-1-yl)piperidin-1-yl)acetyl)amino]propane] is a new, potent and selective nonpeptide neurokinin-1 (NK-1) receptor antagonist. LY303870 bound selectively and with high affinity to human peripheral (Ki = 0.15 nM) and central (Ki = 0.10 nM) NK-1 receptors. LY303870 inhibited [125I]substance P (SP) binding to guinea pig brain homogenates with similar affinity; however, it had approximately 50-fold lesser affinity for rat NK-1 sites. The less active enantiomer, LY306155 [(S)-1-[N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4- (piperidin-1-yl)piperidin-1-yl)acetyl)amino]-propane], was 1,000- to 15,000-fold less potent in all the species examined. LY303870 antagonized in vitro NK-1 receptor effects as demonstrated by blockade of SP-stimulated phosphoinositide turnover in UC-11 MG human astrocytoma cells (Ki = 1.5 nM) and interleukin-6 secretion from U-373 MG human astrocytoma cells (Ki = 5 nM). In addition, LY303870 inhibited SP-induced rabbit vena cava contractions (pA2 = 9.4) with high (50,000-fold) selectivity vs. NK-2 or NK-3 receptor-mediated responses. In vivo, LY303870 inhibited [Sar9,Met(O2)11]-SP induced guinea pig bronchoconstriction (ED50 = 75 micrograms/kg i.v.) and pulmonary microvascular leakage in the bronchi (ED50 = 12.8 micrograms/kg i.v.) and trachea (ED50 = 18.5 micrograms/kg i.v.). Therefore, LY303870 is a potent and selective NK-1 receptor antagonist in vitro and in vivo. The use of LY303870 will facilitate a better understanding of NK-1 receptors in physiological processes.
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PMID:Pharmacological characterization of LY303870: a novel, potent and selective nonpeptide substance P (neurokinin-1) receptor antagonist. 747 61

Two classes of structurally different tachykinin neurokinin3 (NK3) antagonists were used to evaluate species difference in antagonist binding between human and rat NK3 receptors. In competition binding experiments with [125I-MePhe7]NKB as radioligand, PD 154740, PD 157672, SR 48968, and SR 142801 displayed lower Ki values for the human NK3 receptor (40 +/- 4, 12 +/- 1,350 +/- 50, and 0.40 +/- 0.05 nM, respectively) than for the rat NK3 receptor (2450 +/- 130, 288 +/- 25, > 10,000, and 11.0 +/- 0.5 nM, respectively). Data from in vitro functional assay showed similar species preference as observed with the competition binding assay. It was shown previously that substitution of only two amino acid residues in the rat receptor to their human counterparts could change the species selectivity of SR 48968, a weak NK3 antagonist. In the double-substituted rat mutant, all three antagonists (PD 154740, PD 157672, and SR 142801) displayed Ki values (76 +/- 8, 16 +/- 2, and 0.50 +/- 0.05 nM, respectively) very similar to the Ki values for the wild-type human NK3 receptor. Thus, in addition to their previously reported effects on SR 48968, these two amino acid residues are responsible for the species selectivity of these three additional NK3 antagonists. Because PD 154740 and PD 157672 are very different structurally from SR 48968 and SR 142801, our results indicate that the two identified residues may be involved in adopting a receptor conformation that favors the binding of NK3 antagonists that display species preference for the human NK3 receptor.
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PMID:Two classes of structurally different antagonists display similar species preference for the human tachykinin neurokinin3 receptor. 747 98

The pharmacological effects of substance P (SP), neurokinin A (NKA), an amino terminal fragment of SP and related tachykinin receptor agonists on renal resistance vessels were assessed in isolated rat kidney perfused at constant rate (3 ml min-1 g-1 of tissue) with a modified Krebs-Ringer bicarbonate buffer. At a basal perfusion pressure (PP) of 75 +/- 6 mm Hg (n = 5), bolus injections of SP (1-33.3 nmol) had no significant vasoactive effect. After a sustained increase in base-line PP (134 +/- 10 mm Hg) produced by 1 microM phenylephrine, SP evoked a dose-dependent increase in PP. The largest dose of SP increased PP by 60 +/- 5 mm Hg. Physalaemin and kassinin had similar effects as SP but caused a smaller increase in PP at the largest dose. NKA was less potent than the other tachykinins. The vasoconstrictor response to SP was not blocked by 1 microM phentolamine when angiotensin II (0.22-0.26 microM) was used to increase basal tone (n = 5). Thus, the response to SP is not mediated by norepinephrine. The N-terminal SP fragment, SP(1-7), had no effect on PP, which suggested that the pressor response to SP is C-terminal dependent and tachykinin receptor mediated. The selective NK-1 receptor agonist, [Sar9,Met(O2)11]SP, had no significant effect on PP. By contrast, the selective NK-2 and NK-3 receptor agonists, GR64349 and [MePhe7]NKB, produced concentration-dependent pressor responses and were more potent than SP (116 +/- 8 and 134 +/- 15 mm Hg increases in PP at 33.3 nmol, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pharmacological characterization of the pressor response to tachykinins in isolated perfused rat kidney. 750 28

Intracerebroventricular (i.c.v.) injections of senktide (0.01-10 nmol), a tachykinin NK-3 agonist, had an antidiuretic action in water-loaded rats (4.5% body wt.). Pretreatment with OPC-31260 (1 mg/kg, i.v.), a non-peptide vasopressin V2 antagonist, inhibited the antidiuretic action induced by exogenous arginine vasopressin (AVP, 0.1 micrograms/kg, i.v.) and senktide (0.1 nmol, i.c.v.). In addition, senktide (11.8 nmol, i.c.v.) caused a marked increase of the plasma AVP level in conscious rats. These results suggest that the central NKB analogue senktide has an antidiuretic effect by stimulating AVP secretion from the pituitary gland through the NK-3 receptor in the hypothalamus.
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PMID:Central administration of senktide, a tachykinin NK-3 agonist, has an antidiuretic action by stimulating AVP release in water-loaded rats. 750 13

The selective agonists of tachykinin NK1, NK2 and NK3 receptors, respectively [Pro9]substance P, [Lys5,MeLeu9,Nle10]neurokinin A-(4-10) and senktide, stimulated phosphoinositide breakdown in slices of the guinea pig ileum. This was also the case with septide which has recently been found to act on a new type of tachykinin receptors in this tissue. The NK1, NK2 and septide-evoked responses were completely antagonized in the combined presence of (+/-)-CP-96,345 and MEN 10,376 which are potent and selective antagonists of tachykinin NK1 and NK2 receptors respectively in the guinea pig ileum. Like senktide, other available NK3 receptor agonists, such as [MePhe7]neurokinin B, [MeVal7]neurokinin B, [Pro7]neurokinin B and DiMe-C7, stimulated phosphoinositide hydrolysis in either the absence or combined presence of (+/-)-CP-96,345 and MEN 10,376, although senktide was the most potent. Therefore, following the blockade of tachykinin NK1, NK2 and septide-sensitive receptors, the accumulation of inositol monophosphate appears to be a valuable, rapid and sensitive bioassay for determining the activity of NK3 receptor agonists and putative NK3 receptor antagonists.
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PMID:A new selective bioassay for tachykinin NK3 receptors based on inositol monophosphate accumulation in the guinea pig ileum. 750 59

1. We evaluated the effects of neurokinins, tachykinin analogues, or capsaicin on passive membrane properties of guinea-pig bronchial parasympathetic neurones using intracellular recording techniques. 2. Substance P (SP) and the tachykinin analogue, acetyl-[Arg6,Sar9,Met(O2)11]-SP(6-11) (ASMSP), at concentrations selective for the neurokinin (NK)-1 receptor subtype, depolarized the resting potential (3 and 5 mV, respectively) with no change in input resistance. Neurokinin A and beta Ala8NKA(4-10), at concentrations selective for the NK-2 receptor subtype (0.1 microM), were without effect. 3. Neurokinin B (NKB) and [Asp5,6,methyl-Phe8]SP(5-11) (senktide analogue), at concentrations selective for NK-3 receptor subtype, elicited maximum depolarizations of 16 +/- 2 mV for both agonists. The peak of the depolarization was associated with an decrease in membrane resistance (35 +/- 4 and 50 +/- 7%, respectively). 4. Capsaicin (1 microM) elicited a 3-24 mV depolarization of the resting potential of thirteen of eighteen bronchial ganglion neurones and decreased the input resistance of seven of thirteen of these neurones. The effects of capsaicin were reduced by desensitization with senktide analogue at a concentration selective for the NK-3 receptor subtype, whereas a non-peptide NK-1 receptor antagonist had no effect. 5. Using voltage clamp analysis, capsaicin and senktide analogue evoked an inward current and an increase in membrane conductance at the resting membrane potential. The reversal potential for senktide analogue was estimated to be + 4 mV. 6. These data support the hypothesis that neurokinin-containing nerve terminals are localized within guinea-pig bronchial parasympathetic ganglia and, when released, the predominant effect of the neurokinins is by activation of NK-3 receptors.
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PMID:Electrophysiological effects of tachykinins and capsaicin on guinea-pig bronchial parasympathetic ganglion neurones. 750 8

The regulation of tachykinin-evoked acetylcholine release by the dopaminergic system in the neostriatum was examined. We studied the effect of selective and potent tachykinin agonists for each subtype of receptor ([Sar9,Met(O2)11]-Substance P for NK1; [Nle10]-Neurokinin A4-10 for NK2; and senktide for NK3) on endogenous acetylcholine release from rat striatal slices where the dopaminergic system was modified either by 6-hydroxydopamine lesion or by dopamine receptor antagonists. Unilateral 6-hydroxydopamine lesion of the nigrostriatal pathway induced a decrease in senktide-evoked acetylcholine release and an increase in the effect of [Nle10]-Neurokinin A4-10. The same results were obtained after chronic haloperidol treatment, whereas SCH-23390 or clozapine treatment had no effect on tachykinin-evoked acetylcholine release, suggesting an involvement of D2 receptors. 6-hydroxydopamine lesion induced a diminution in the density of NK3 receptor, which could be related to the reduction in senktide-evoked acetylcholine release.
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PMID:Control of tachykinin-evoked acetylcholine release from rat striatal slices by dopaminergic neurons. 750 58

The effects of ageing on tachykinin-induced behaviours and tachykinin receptors were investigated in the rat. Infusion of the NK-3 tachykinin agonist senktide (0.25, 0.5 and 1 nmol) into the substantia nigra induced locomotion in young (4-6 months) animals but this response was attenuated in middle-aged (12 months) and old (27 months) animals. In contrast, senktide-induced wet dog shakes were not significantly affected by age. In the ventral tegmental area, senktide induced locomotion and wet dog shakes with bell-shaped dose-response curves which were unaffected by age. Senktide suppressed grooming but the effect reached significance in the older animals only. Quantitative receptor autoradiography revealed no effect of age on NK-1 tachykinin receptor density in the striatum while NK-3 receptor density declined in the ventrolateral striatum and to a nonsignificant degree in the substantia nigra but not in other striatal subregions or the ventral tegmental area. We conclude that ageing of the nervous system is not associated with widespread changes in tachykinin binding but differences in behavioural response to tachykinin agonists may reflect changes in other transmitter systems which respond to tachykinin input.
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PMID:Effects of ageing on tachykinin function in the basal ganglia. 751 76


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