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)

Our previous study showed that microinjection of substance P (SP) into caudate nucleus inhibits gastric myoelectric fast wave and gastric motility, an effect mediated by muscarinic receptor. The present investigation showed that this effects of SP could be blocked by coinjected SP antiserum or SP antagonist [Arg6, D-Trip7,9, MePhe8]-SP6-11 or D2 dopamine antagonist haloperidol. In addition, microinjection of dopamine (DA) into caudate nucleus could also inhibit gastric fast wave and motility, an effect again being blockable by coinjected DA antagonist haloperidol or atropine. Thus, it appears that the muscarinergic inhibitory effect of SP on gastric fast wave and motility is mediated by D2 dopamine receptor.
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PMID:[Participation of dopamine on the muscarinergic inhibitory effect of substance P on gastric myoelectric activity and motility]. 757 Jan 9

Analogues of [Orn6]-SP6-11 have been synthesized in which the Met11-NH2 residue is replaced by the alpha, gamma-dimethyl, alpha, gamma-dibenzyl and alpha, gamma-di-tert-butyl esters of glutamic acid. These analogues were tested in three in vitro preparations representative of NK-1, NK-2 and NK-3 receptor types for agonist and antagonist activity. The dimethyl analogue is a selective full agonist in the NK-1 receptor type and a weak antagonist in the other two receptor types, while the dibenzyl and the di-tert-butyl analogues are potent antagonists in the NK-1 receptor type and weak antagonists in the other two receptor types. It is concluded that appropriate modification at the alpha-carboxamide and the side chain of the methionine residue of substance P may induce antagonism without using D-amino acids.
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PMID:Synthesis of potent antagonists of substance P by modifying the methionyl and glutaminyl residues of its C-terminal hexapeptide and without using D-amino acids. 768 61

Neurokinin binding sites are distributed throughout the central and peripheral nervous system and three neurokinin binding sites have been described until now. The endogenous tachykinins substance P, neurokinin A and eledoisin as well as the highly selective neurokinin ligands [Arg6, Sar9, Met(O2)11]SP6-11 and [Sar9, Met(O2)11]SP (for neurokinin-1), MEN 10,376 and [beta Ala8]NKA(4-10) (for neurokinin-2) and senktide and [MePhe7]NKB (for neurokinin-3) were used for displacement experiments. Neurokinin-1 and -3 binding sites were demonstrated in membrane preparations of rat striatum, frontal cortex, hypothalamus, hippocampus and amygdala by displacing [125I]-BH-substance P and [125I]-BH-eledoisin, respectively. The highly selective neurokinin-2 ligand MEN 10,376 was iodinated to measure neurokinin-2 binding sites, but no specific binding was found in membranes of all brain regions, the spinal cord, the stomach, the urinary bladder or the guinea-pig lung, probably due to loss of binding properties. We conclude that neurokinin-1 and neurokinin-3 binding sites are distributed in several brain regions of the rat brain and selective neurokinin ligands are important tools to characterize neurokinin binding sites.
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PMID:Characterization of neurokinin binding sites in rat brain membranes using highly selective ligands. 769 43

This study has examined the abilities of (+/-)-CP96345 and (+/-)-SR48968, nonpeptide antagonists selective for the tachykinin NK1 and NK2 receptors, respectively, to block bronchoconstriction caused by intravenous administration of direct-acting receptor agonists and the indirect-acting mimetics capsaicin, serotonin and 2-methyl-serotonin in the anesthetized guinea pig. The NK1 antagonist (+/-)-CP96345 was found to cause, at a maximally tolerated dose of 9 mumol/kg, an approximate 10-fold rightward shift of the dose-response curves for selective NK1 agonists substance P (SP), [Sar9,Met(O2)11]SP and Ac-[Arg6,Sar9,Met(O2)11]SP6-11 without altering responses to selective NK2 agonists neurokinin A (NKA), [Nle10]NKA4-10 or [beta-Ala8]NKA4-10. The NK2 antagonist (+/-)-SR48968 caused dose-dependent rightward shifts of the dose-response curves for the NK2 but not the NK1 agonists. Results using combinations of the receptor antagonists indicate that the NK2 agonists could cause bronchoconstriction by acting on the NK1 receptors at large doses relative to those used without antagonists. Of the agonists used here, [beta-Ala8]NKA4-10 appeared to be the most selective for the NK2 receptors. When used alone, only (+/-)-SR48968 was found to block bronchoconstriction caused by capsaicin, serotonin (after blockade of 5-HT2 receptors by LY53857) and 2-methyl-serotonin. When (+/-)-CP96345 was also given, larger additional blockade was seen with capsaicin than with serotonin or 2-methyl-serotonin as mimetic substance. Atropine caused small and variable degrees of blockade of serotonin and 2-methyl-serotonin but not of capsaicin after combinations of the two antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Differential blockade by tachykinin NK1 and NK2 receptor antagonists of bronchoconstriction induced by direct-acting agonists and the indirect-acting mimetics capsaicin, serotonin and 2-methyl-serotonin in the anesthetized guinea pig. 826 78

Bilateral intranigral administration of the selective NK-1 tachykinin receptor agonist [AcArg6, Sar9, Met(O2)11]SP6-11 (0-1 nmol total bilateral dose) selectively induced grooming in rats. This response was blocked by concurrent intranigral administration of the NK-1 tachykinin receptor antagonist RP 67580 (2 nmol), but not by NK-2 (L-659,877) or NK-3 ([Trp7, beta-Ala8]NKA4-10) antagonists. Pretreatment with systemic opioid (naloxone 1.5 mg/kg) and D1 dopamine (SCH 23390 100 micrograms/kg) receptor antagonists also attenuated tachykinin-induced grooming, which was unaffected by D2 dopamine (sulpiride 30 mg/kg) or 5-HT2A+C (ritanserin 2 mg/kg) antagonists. Grooming induced by intranigral [AcArg6, Sar9, Met(O2)11]SP6-11 was also attenuated by bilateral 6-hydroxydopamine lesions of the substantia nigra. These findings indicate that grooming induced by intranigral tachykinins reflects activation of NK-1 receptors and is dependent upon endogenous dopamine and consequent selective stimulation of D1 dopamine receptors.
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PMID:Pharmacological characterization of grooming induced by a selective NK-1 tachykinin receptor agonist. 862

The application of the concept of backbone cyclization to linear substance P (SP) analogs is presented. We describe the synthesis, characterization, and biological activity of a series of backbone-to-amino-terminus cyclic analogs of the C-terminal hexapeptide of SP. These analogs were designed on the basis of NMR data and molecular modeling of the selective NK-1 analog WS-septide (Ac[Arg6,Pro9]SP6-11). A series of peptides with the general formula: cyclo[-CH2)m-NH-CO-(CH2)n-CO-Arg-Phe-Phe-N-]-CH2-CO-Leu-Met-NH2 (n = 2, 3, 6 and m = 2, 3, 4) was synthesized by solid phase methodology using Fmoc chemistry for the main chain and Boc chemistry for the building units [Na-(omega-aminoalkyl)Gly] side chains. Cyclization was performed on the resin after removal of the Boc protecting group from the omega-aminoalkyl chain. Cyclic and precyclic analogs were compared. They were purified by HPLC and characterized by mass spectroscopy and NMR. Biological activity and selectivity to the NK-1 neurokinin receptor were found to depend on cyclization and the ring size: The most active and selective analog had a ring of 20 atoms. This analog was found to have enhanced metabolic stability in various tissue preparation compared to WS-septide.
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PMID:Synthesis and biological activity of NK-1 selective, N-backbone cyclic analogs of the C-terminal hexapeptide of substance P. 875 39

Novel backbone-to-side chain and backbone-to-backbone cyclic analogues of substance P (SP) were prepared by solid-phase synthesis and screened for biological activity. An analogue containing a thioetherlactam ring between positions 9 and 11 showed an EC50 value of 20 nM toward the neurokinin 1 (NK-1) and was inactive toward the NK-2 and NK-3 receptors. On the other hand, in a multiple backbone cyclic peptide library of similar analogues, in which the sulphur was excluded from the ring, very low activity was detected. The activity was re-evaluated and was found to be even lower (EC50 = 0.11 mM) than the previously published data. These results indicate that the thioether moiety has a crucial role in receptor activation. The results also show tolerance of the NK-1 receptor, but not NK-2 or NK-3, to cyclization of the C-terminal portion of the SP6-11 hexapeptide.
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PMID:Backbone cyclization of the C-terminal part of substance P. Part 1: The important role of the sulphur in position 11. 923 34

Substance P (SP) is an important neurotransmitter that mediates various gut functions; however, its precise pathophysiological role remains unclear. In this study, we investigated the effect of SP on colonic function and the effect of TAK-637 [(aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]naphthyridine-6,13-dione] a new neurokinin-1 (NK1) receptor antagonist, on colonic responses to SP or stress in Mongolian gerbils. SP and the selective NK1 agonist [pGlu6]SP6-11 significantly increased fecal pellet output. TAK-637 reduced [pGlu6]SP6-11-induced defecation, but did not significantly affect neurokinin A-, 5-hydroxytryptamine- or carbachol-stimulated defecation. Oral TAK-637 decreased restraint stress-stimulated fecal pellet output with an ID50 value of 0.33 mg/kg. Ondansetron and atropine, but not the peripheral kappa-receptor agonist trimebutine, also reduced restraint stress-stimulated defecation. TAK-637 inhibited the increase in fecal pellet output stimulated by intracerebroventricular injection of corticotropin-releasing factor, but did not affect the stress-induced increase in plasma adrenocorticotropic hormone levels. Denervation of the sensory neurons with capsaicin did not affect stress-stimulated defecation. These results suggest that NK1 receptors in the enteric plexus play an important role in stress-induced changes in colonic function, and that TAK-637 may be useful in the treatment of functional bowel diseases such as irritable bowel syndrome.
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PMID:Effects of TAK-637, a novel neurokinin-1 receptor antagonist, on colonic function in vivo. 1145 17

The present investigation showed that microinjection of substance P (SP) into dorsal vagal nucleus inhibited gastric myoelectric fast wave and gastric motility. The effect could be blocked by SP antiserum or SP antagonist [Arg6, D-Trp7,9, N-Me-Phe8]-SP6-11 or vagotomy. Depletion of sympathetic transmitters by reserpine did not affect induction of the inhibition. The results indicate that both exogenous and endogenous SP of dorsal vagal nucleus decrease the gastric myoelectric fast wave and motility, which is mediated by vagus nerve.
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PMID:[Inhibition of gastric myoelectric activity and gastric motility by microinjection of substance P into dorsal vagal nucleus in rats]. 1149 54


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