Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of substance P, substance P-(1-7) and substance P-(5-11) on endogenous dopamine outflow in rat striatal slices were investigated. The dose-response curves (0.01 nM to 10 microM) were bell-shaped, with significant increases at 0.1 and 1 nM but with no effect at higher concentrations. The tachykinin NK1 receptor agonist, [Sar9,Met(O2)11]substance P, significantly increased dopamine outflow at 10 and 100 nM. The effects of substance P or substance P-(5-11) and 25 mM KCl were additive. A negative interaction was observed with substance P-(1-7) and K+. The increase in dopamine outflow elicited by 1 nM substance P and substance P-(5-11) was reversed by the tachykinin NK1 receptor antagonist WIN 51,708 (17 beta-hydroxy-17 alpha-ethynyl-5 alpha-androstano[3,2-b]pyrimido[1,2- alpha]benzimidazole) (25 and 250 nM), whereas only partial reversal was observed for the effect of substance P-(1-7). These results show that substance P fragments locally modulate striatal dopamine outflow and the mechanisms underlying this modulation may differ between N- and C-terminal fragments.
 ...
PMID:Substance P-(1-7) and substance P-(5-11) locally modulate dopamine release in rat striatum. 749 81

The effects of three tachykinin NK1 receptor antagonists and a tachykinin NK2 receptor antagonist against substance P-induced contractions of the guinea-pig proximal colon longitudinal muscle were investigated. Atropine, tetrodotoxin and phosphoramidon did not affect the concentration-response curve for substance P (pEC50 = 7.8). The tachykinin NK1 receptor antagonist, 2S,3S-cis-CP 96345, competitively inhibited the contractions due to substance P (pA2 = 8.5; constrained pA2 = 8.9), but at higher concentrations (> or = 3 x 10(-7) M), 2S,3S-cis-CP 96345 also depressed the concentration-response curve for methacholine. The species-selective tachykinin NK1 receptor antagonists, WIN 51708 and WIN 62577 (both 1 x 10(-6) M), and the tachykinin NK2 receptor antagonist, SR 48968 (3 x 10(-7) M), had no effect. It is concluded that substance P induces contractions through the stimulation of tachykinin NK1 receptors on the smooth muscle cells. In this preparation, tachykinin NK2 receptors do not seem to be involved in the contractile action of substance P.
 ...
PMID:Substance P-induced contractions of the guinea-pig proximal colon through stimulation of post-junctional tachykinin NK1 receptors. 750 52

WIN 64821, a nonpeptide neurokinin antagonist, was isolated from a strain of Aspergillus sp., SC319. The compound was produced in different fermentation media with greatest yields observed when the culture was grown in a synthetic medium supplemented with L-tryptophan and L-phenylalanine. After 6 days fermentation, yields greater than 600 mg/liter were obtained. Two analogs of WIN 64821 were also identified in the culture extracts and subsequently tested for biological activity. WIN 64821 was the most potent compound isolated from this culture and exhibited activity as a substance P-binding inhibitor with submicromolar potency against the human neurokinin 1 receptor.
 ...
PMID:WIN 64821, a novel neurokinin antagonist produced by an Aspergillus sp. I. Fermentation and isolation. 751 37

WIN 64821, a secondary metabolite produced by Aspergillus sp. (ATCC 74177) was found to inhibit radiolabeled substance P (SP) binding in a variety of tissues, including those of human origin. This compound inhibited, in a competitive manner, the binding of SP with Ki values ranging from 0.24 microM in human astrocytoma U-373 MG cells to 7.89 microM in rat submaxillary membranes. Additionally, WIN 64821 was found to inhibit 125I-NKA binding to the NK2 receptor in human tissue at a concentration equivalent to its NK1 activity (0.26 microM). The inhibitory activity of WIN 64821 against an NK3 selective ligand, 3H-senktide, was found to be much weaker (Ki = 15.2 microM). WIN 64821 was also evaluated in NK1 functional assays and was found to be a competitive antagonist of SP-induced contractility in the guinea pig ileum (pA2 = 6.6) as well as an inhibitor of SP-induced 45Ca2+ efflux from human astrocytoma U-373 MG cells (IC50 = 0.6 microM). In a rat vas deferens model, WIN 64821 inhibited eledoisin-induced contractility with an IC50 of 3.4 microM indicating functional antagonism at the NK2 receptor. The data presented in this study provide biochemical, pharmacological and functional evidence supporting WIN 64821 as a competitive neurokinin antagonist.
 ...
PMID:WIN 64821, a novel neurokinin antagonist produced by an Aspergillus sp. II. Biological activity. 751 38

WIN 64821 (1) is a substance P (SP) antagonist isolated from a fungal culture (Aspergillus sp., SC319). It is a symmetrical dimer biosynthesized from four aromatic amino acid molecules: each equivalent half of the dimer is constructed from one molecule of phenylalanine (Phe) and one molecule of tryptophan (Trp). Feeding analogs of Phe, Trp, and other amino acids to intact cells of SC319 has yielded 36 biosynthetic analogs of WIN 64821. The analogs fall into three categories: substitutions on the indoline ring, substitutions on the Phe-derived phenyl ring, and replacement of the phenyl ring by an aliphatic group. In addition, these directed biosynthesis experiments generated asymmetrical dimers (derived from three amino acids) and, often, symmetrical dimers (derived from two amino acids). The relative SP binding affinities of several analogs suggest involvement of both the indoline and phenyl moieties in SP receptor binding.
 ...
PMID:WIN 64821, a novel neurokinin antagonist produced by an Aspergillus sp. III. Biosynthetic analogs. 751 39

We investigated the effects of intracerebroventricular injection of substance P (SP) on the scopolamine (1 mg/kg)-induced impairment of spontaneous alternation performance in the mouse. SP (0.001-3 micrograms) alone did not influence either spontaneous alternation performance or total arm entries. Scopolamine (1 mg/kg) impaired spontaneous alternation performance accompanied by an increment in total arm entries. In contrast, SP (0.01-1 micrograms) significantly improved the scopolamine (1 mg/kg)-induced impairment of spontaneous alternation performance without influencing the scopolamine (1 mg/kg)-induced increase in total arm entries. The effects of SP (0.1 micrograms) on the scopolamine (1 mg/kg)-induced impairment of spontaneous alternation performance were almost completely reversed by pretreatment with WIN 62577 (1 mg/kg), a tachykinin NK-1 receptor antagonist. These results suggest that SP improves the scopolamine-induced impairment of spontaneous alternation performance through the mediation of tachykinin NK-1 receptors.
 ...
PMID:Substance P markedly ameliorates scopolamine-induced impairment of spontaneous alternation performance in the mouse. 754 97

Activation of dopamine D1 receptors is thought to stimulate release of striatal acetylcholine (ACh) indirectly, possibly through local release of substance P which, in turn, may enhance release of ACh. To test this hypothesis, in vivo microdialysis was used to assess the effect of neurokinin1 (NK1) receptor blockade on D1 agonist-induced increases in ACh release in the striatum of awake, freely moving rats with and without a unilateral 6-hydroxydopamine-induced lesion of the nigrostriatal pathway. Local perfusion with the D1 agonist (+-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3- benzazepine-7,8-diol hydrochloride (SKF 38393; 1-25 microM for 20 min) increased striatal ACh release in both intact rats and rats with a 6-hydroxydopamine-induced lesion, although the increase was greater in magnitude in rats with a lesion. Local application of the NK1 antagonist, (2S,3S)-cis-2-(diphenylmethyl)-N- [(methoxyphenyl)methyl]-1-azabicyclo[2.2.2]octan-3-amine (CP-96,345; 10 and 25 microM), but not its less active enantiomer (2R,3R)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)methyl]-1- azabicyclo[2.2.2]octan-3-amine (CP-96,344; 10 and 25 microM), decreased the elevation in ACh induced by SKF 38393 in both intact rats and rats treated with 6-hydroxydopamine. Systemic administration of the NK1 antagonist 17-beta-hydroxy-17-a-androstanol[3.2- b]pyrimidol[1,2-a]benzimidazole hydrochloride (WIN 51,708; 20 mg/kg i.p.) also reduced the increase in ACh release induced by local perfusion of SKF 38393.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Dopamine D1 receptor-stimulated release of acetylcholine in rat striatum is mediated indirectly by activation of striatal neurokinin1 receptors. 791 77

WIN 51708 is a nonpeptide antagonist of the neurokinin (NK)-1 (substance P) receptor that possesses a dramatically higher affinity for the rat NK-1 receptor, compared with the human NK-1 receptor. This selectivity is the opposite of the selectivity displayed by CP-96,345 and is much greater in magnitude than the selectivity of RP 67580. The naturally occurring peptide agonist substance P shows no such species selectivity. To determine the molecular basis for the species selectivity of WIN 51708, a series of chimeric and point-mutated NK-1 receptors were created and functionally expressed in Chinese hamster ovary cells. Residue 97 in the first extracellular loop and residue 290 in the seventh putative transmembrane domain are critical determinants for the selectivity of WIN 51708 for the rat over the human NK-1 receptor. Although mutation of either residue 97 or residue 290 in the rat NK-1 receptor is sufficient for a low, human-like affinity for WIN 51708, both of these residues must be simultaneously mutated in the human NK-1 receptor to allow nearly rat wild-type affinity for this antagonist. This suggests that the binding environment for WIN 51708 in the rat NK-1 receptor differs, at least in part, from the binding environment in the human NK-1 receptor. In addition, although residue 290 is critical for the species selectivity of WIN 51708 and CP-96,345, residue 97 does not play a role in the species selectivity of CP-96,345. These data support a model in which the binding environments for WIN 51708 and CP-96,345 in part differ.
 ...
PMID:Both extracellular and transmembrane residues contribute to the species selectivity of the neurokinin-1 receptor antagonist WIN 51708. 805 46

The naturally occurring tachykinins, substance P, neurokinin A and neurokinin B, induce the formation of inositol phosphates or cAMP in a variety of tissues but their effects on neurons have not been resolved. We used primary cultures of neonatal rat spinal cord to determine whether neurokinin receptors mediate changes in these second messengers in spinal neurons. We found that substance P, neurokinin A and neurokinin B induced the formation of inositol phosphates in a concentration-dependent manner with similar potencies (EC50S: 3.6, 5.7 and 21.3 nM, respectively), but at concentrations tested (0.1-1.0 microM) these peptides had no effect on cAMP levels. All three tachykinins induced the formation of inositol phosphates predominately by activation of neurokinin1 receptors. CP-96,345 and WIN 51,708, neurokinin1 receptor antagonists, attenuated the response to substance P, neurokinin A and neurokinin B. GR 103,537, a neurokinin2 receptor antagonist, had no effect on the responses induced by any of the tachykinins. Furthermore, the selective neurokinin1 receptor agonist, GR-73632, induced the formation of inositol phosphates in a concentration-dependent manner, whereas the selective neurokinin2 receptor agonist, GR-64349, generated inositol phosphates only at the highest concentration tested (10 microM). Senktide, a neurokinin3 receptor agonist, did not induce the formation of inositol phosphates at any of the concentrations tested (0.01-10 microM). Inositol phosphate formation appeared to be due to a direct effect of the tachykinins on neuronal neurokinin1 receptors. These results suggest that biological responses in spinal neurons following activation of neurokinin1 receptors are mediated mainly by the hydrolysis of phosphoinositol 4,5-bisphosphate to form inositol 1,4,5-trisphosphate and diacylglycerol. It remains to be determined which of these second messengers mediates the increased neuronal excitability and depolarization that occurs in response to substance P.
 ...
PMID:Tachykinins alter inositol phosphate formation, but not cyclic AMP levels, in primary cultures of neonatal rat spinal neurons through activation of neurokinin receptors. 857 79

Neuropeptide gamma (NP gamma) is a 21 aminoacid peptide belonging to the tachykinin (TK) family and including neurokinin A (NKA) in its C-terminal sequence. NP gamma possesses higher affinity than NKA for central NK-2 receptors; it shows lower affinity for NK-1 receptors, however, it potently stimulates salivary secretion, which is mediated by NK-1 receptor activation. Pulse intracerebroventricular (pICV) injection of TKs selectively inhibits water intake in rats. Our studies have suggested that NK-1 receptors may mediate the inhibition of angiotensin II-induced drinking, while NK-2 receptors that of drinking induced by cell dehydration. The present study evaluated the effect of pICV injections of NP gamma on water intake in rats. The injection of NP gamma, 8-250 ng/rat, markedly inhibited angiotensin II-induced drinking, and its effect was blocked by the NK-1 receptor antagonist WIN 62577. NP gamma potently inhibited also drinking induced by SC hypertonic NaCl load or water deprivation. The threshold dose for these effects was 31 ng/rat. Also carbachol-induced drinking was inhibited, but at higher doses. On the other hand, NP gamma did not modify food intake in food deprived rats or 0.1% saccharin intake in water and food sated rats, at the same doses effective on drinking. Present findings support the idea that TKs selectively inhibit water intake in rats and are in keeping with our hypothesis that NK-1 and NK-2 receptors mediate, respectively, inhibition of angiotensin II- and cell dehydration-induced drinking.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Neuropeptide gamma: a mammalian tachykinin endowed with potent antidipsogenic action in rats. 858 70


1 2 3 4 Next >>