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)

An extract of the whole brain of the alligator (Alligator mississipiensis) contained very high concentrations of substance P-like immunoreactivity (405 pmol/g wet tissue) and neurokinin A-like immunoreactivity (514 pmol/g), as measured with antisera raised against the mammalian peptides. The primary structure of alligator substance P was established as: Arg-Pro-Arg-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2. This sequence is the same as that of chicken substance P and shows one substitution (Arg for Lys3) as compared with mammalian substance P. The neurokinin A-like immunoreactivity was separated into two components. Neuropeptide gamma was the most abundant peptide and its primary structure was established as Asp-Ala-Gly-Tyr-Gly-Gln-Ile-Ser-His-Lys-Arg-His-Lys-Thr-Asp-Ser- Phe-Val-Gly-Leu-Met-NH2. This sequence shows one substitution (Tyr for His4) compared with mammalian neuropeptide gamma. The second component was identical to mammalian neurokinin A. A peptide with the chromatographic properties of mammalian neuropeptide K was not identified in the extract.
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PMID:Structural characterization of tachykinins (neuropeptide gamma, neurokinin A, and substance P) from a reptile, Alligator mississipiensis. 128 82

The role of the C-terminal residue in the sequence of the NK-2-selective tachykinin antagonist, MEN 10207 (Asp-Tyr-D-Trp-Val-D-Trp-D-Trp-Arg-NH2), has been examined by systematic amino acid substitutions. Biological activity has been measured on two in vitro preparations chosen as paradigms of the recently described NK-2 receptor subtypes, namely the rabbit pulmonary artery and the hamster trachea, in order to define the structural requirements necessary for antagonist subtype selectivity. We conclude that in the presence of a C-terminal hydrophilic residue, affinity is maximal for the NK-2A subtype, while hydrophobic, bulky and aromatic residues increase affinity for the NK-2B subtype.
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PMID:Structure-activity study of the C-terminal residue of MEN 10207 tachykinin antagonist. 132 Feb 65

Experiments were designed to characterize receptor(s) that mediate nonadrenergic, noncholinergic contractions of the guinea pig hilar bronchus using selective neurokinin (NK)1 (CP 96,345) and NK2 (R396 and MEN 10,376) tachykinin receptor antagonists. Left and right hilar bronchi were studied as pairs in the presence of atropine, propranolol, phentolamine; indomethacin and thiorphan. (2S, 3S)-cis-2-(diphenylmethyl)-N-(2-methoxyphe nyl)-1-azabicyclo[2,2,2]octan-3-amine (CP 96,345) selectively antagonized contractions of the bronchus to the NK1 agonist Ac-[Arg6,Sar9,Met(O2)11]-SP(6-11) with a -log molar KB value of about 8.0. Similarly, Ac-Leu-Asp-Gln-Trp-Phe-Gly-NH2 (R396) and [Tyr5, D-Trp6,8,9, Lys10]-NKA(4-10) (MEN 10,376) selectively antagonized contractions to the NK2 agonist [beta Ala8]-NKA(4-10) with -log molar KB values of about 5.5 and 6.7, respectively. CP 96,345 (3 x 10(-7) M) had no effect on contractions evoked by transmural electrical stimulation (TES). However, both R396 (1 x 10(-5) to 1 x 10(-4) M) and MEN 10,376 (1 x 10(-6) to 1 x 10(-5) M) caused blockade of responses to TES. CP 96,345 (3 x 10(-7) M) antagonized TES-induced contractions only when studied after substantial blockade by R396 or MEN 10,376. Contractions to TES were not abolished by R396, MEN 10,376 or a combination of these antagonists with CP 96,345. R396 (1 x 10(-6) M) increased the maximum contraction to TES and potentiated the frequency-response curve in bronchi treated with MEN 10,376 (1 x 10(-6) M).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Nonadrenergic, noncholinergic contractile responses of the guinea pig hilar bronchus involve the preferential activation of tachykinin neurokinin2 receptors. 132 30

We have assessed the affinity of R 396 (Ac. Leu-Asp-Gln-Trp-Phe-Gly NH2) in a number of NK-2 tachykinin receptor bearing-tissues from several species. The cyclic analog of R 396, (MEN 10354) was less potent and selective than the linear hexapeptide at NK-2 tachykinin receptors subtypes in the rabbit pulmonary artery and hamster trachea. The affinity of R 396, as measured by a smooth muscle contraction assay and a radioligand binding assay, was higher (about 10 fold) for NK-2 receptors expressed in hamster tissues (urinary bladder, stomach and trachea) than in rat tissues (urinary bladder, vas deferens, colon and stomach) and a further drop in affinity was observed in bovine tissues (urinary bladder and stomach) or rabbit bronchus. The results are discussed in relation to the proposed existence of NK-2 receptor subtypes and raise the question of the existence of species-related differences as compared to the existence of true receptor subtypes.
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PMID:Affinity of R 396, an NK-2 tachykinin receptor antagonist, for NK-2 receptors in preparations from different species. 132 23

A tachykinin peptide was isolated from an extract of the intestine of the European green frog, Rana ridibunda, and its primary structure was established as: His-Lys-Leu-Asp-Ser-Phe-Ile-Gly-Leu-Met.CONH2. This sequence was confirmed by chemical synthesis and shows two amino acid substitutions (leucine for threonine at position 3 and isoleucine for valine at position 7) compared with neurokinin A. Binding parameters for synthetic [Leu3,Ile7]neurokinin A and mammalian tachykinins were compared using receptor-selective radioligands and crude membranes from tissues enriched in the NK1, NK2 and NK3 receptors. [Leu3,Ile7]Neurokinin A was approx. 3-fold less potent than substance P in inhibiting the binding of 125I-labelled [Sar9,Met(O2)11]substance P (labelled with Bolton-Hunter reagent) to rat submandibular gland (NK1 receptor), 8-fold less potent than neurokinin A in inhibiting the binding of [2-[125I]iodohistidine1]neurokinin A to rat stomach fundus (NK2 receptor) and 6-fold less potent than neurokinin B in inhibiting the binding of 125I-Bolton-Hunter-labelled scyliorhinin II to rat brain (NK3 receptor). Thus the frog neurokinin A-related peptide shows moderate affinity but lack of selectivity for all three tachykinin-binding sites in rat tissues. This non-selectivity is similar to that displayed by the molluscan tachykinin, eledoisin, which also contains an isoleucine residue in the corresponding position in the molecule.
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PMID:Primary structure and receptor-binding properties of a neurokinin A-related peptide from frog gut. 133 83

Three N-terminal fragments of the selective tachykinin NK-2 receptor antagonist MEN 10376 (H-Asp-Tyr-DTrp-Val-DTrp-DTrp-Lys-NH2) have been synthesized and tested in several mammalian tissues in order to establish the minimum length of the peptide chain for maintenance of the antagonist activity. Biological activity has been determined on the rabbit pulmonary artery (RPA) and hamster trachea (HT) preparations, chosen as representative of the NK-2A and NK-2B receptor subtypes, respectively, and on the rabbit bronchus (RB), guinea-pig bronchus (GPB), human urinary bladder (HuUB), human ileum (HuI) and human colon (HuC) preparations to verify the previously described NK-2A character of these tissues. The N-terminal tetrapeptide was inactive in the RPA and HT, while the N-terminal hexa- and penta- peptides maintained antagonist activity in all preparation investigated. The selectivity of the latter two peptides confirms that the receptor expressed in RB, GPB, HuUB, HuC and HuI tissues is of the NK-2A type.
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PMID:N-terminal truncated analogs of men 10376 as tachykinin NK-2 receptor antagonists. 133 61

We report on a structure-activity study of R396 (Ac-Leu-Asp-Gln-Trp-Phe-Gly-NH2), a linear hexapeptide tachykinin antagonist selective for the putative NK2B receptor subtype. Asp2, Trp4 and the C-terminal glycinamide have been challenged by classical amino acid substitutions with the aim of elucidating the structural requirements responsible for NK2 subtype selectivity. The biological activities indicate that Asp2 has a crucial role for the high affinity of R396 at the NK2B subtype: none of the analogues substituted in position 2 display higher affinity as compared to R396, regardless of the nature of the residue introduced. Trp4 has been replaced by other aromatic residues, again yielding weak antagonist or inactive compounds. Finally, the C-terminal amide appears to be crucial for affinity, the free acid analogue being devoid of biological activity. On the other hand, antagonistic activity is maintained both by the desGly pentapeptide and by the analogue bearing beta Ala in place of Gly in position 6. In conclusion, since the NK2B selectivity pattern was maintained throughout the whole series of R396 replacement analogues, we speculate that the overall conformational features of this family of linear hexapeptides favour the interaction with the NK2B receptor subtype.
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PMID:Structure-activity relationship study of R396, an NK2 tachykinin antagonist selective for the NK2B receptor subtype. 133 33

1. In the presence of atropine, mepyramine and ranitidine, electric field stimulation of the guinea-pig isolated ileum longitudinal muscle-myenteric plexus preparation resulted in a two component non-adrenergic non-cholinergic contraction. The initial contraction had a duration of approximately 1 s whereas the second contraction lasted approximately 10 s. The second contraction was completely inhibited by tetrodotoxin (0.2 x 10(-6) M) with minimal effect on the initial contraction. Phentolamine (3 x 10(-6) M), propranolol (3 x 10(-6) M) and hexamethonium (10(-4) M), did not significantly reduce either component of the contractile response. 2. The neurokinin NK1 receptor antagonists, GR82334 and GR71251, produced concentration-related (EC50 = 564 and 173 nM respectively) inhibitions of the second contraction with no effect on the initial contraction. The neurokinin NK2 receptor antagonists MEN 10207 and Ac-Leu-Asp-Gln-Trp-Phe-Gly-NH2 (R 396), 1 x 10(-9)-10(-5) M, were without effect on either component of the contractile response. 3. Concentration-related inhibitions of the second contraction, with no effect on the initial contraction, were observed after inclusion of the histamine H3 receptor agonists (R)-alpha-methylhistamine (pD2 = 7.6), N alpha-methylhistamine (pD2 = 7.7) and N alpha,N alpha-dimethylhistamine (pD2 = 6.3). Histamine also inhibited the second contraction (pD2 = 6.2) in a concentration-related manner but produced a lower maximum inhibitory effect than the other agonists tested. 4. Inclusion of the H3 receptor antagonists, thioperamide, burimamide, impromidine and phenylbutanoylhistamine, caused parallel concentration-related rightward shifts in the concentration-response curve to (R)-alpha-methylhistamine. In each case, Schild analysis of these data gave slopes not significantly different from unity. Antagonist affinity values for thioperamide (pA2 = 8.2), burimamide (pA2 = 7.0) and impromidine (pA2 = 7.0) were consistent with values obtained in other assays of the H3 receptor. However, phenylbutanoylhistamine (pA2 = 5.8) and betahistine (pKB < 4) had affinities more than ten fold lower than values obtained in other assays of the H3 receptor.5. Exposure of the tissues to N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (10-6 M) for 7-30min followed by extensive washing, had no effect on basal contractions, but produced a rightward shift in the concentration-response curves to (R-alpha-methylhistamine, Nalpha"-methylhistamine, Nalpha",Nalpha-dimethylhistamine and histamine. This treatment also resulted in a decrease in the maximum inhibitory response obtainable. Apparent agonist affinity (pKD) values of 7.01, 7.06, 6.09 and 6.13 were estimated for (R)-alpha-methylhistamine, Nalpha-methylhistamine, Nalpha',Nalpha"-dimethylhistamine and histamine respectively.6. In conclusion, pharmacological analysis has revealed that histamine H3 receptors in the guinea-pig ileum modulate the release of non-adrenergic non-cholinergic neurotransmitters, one of which is probably substance P. In addition we have identified N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline as an irreversible antagonist at H3 receptors and have used this compound to estimate apparent affinity values of agonists at H3 receptors in this preparation.
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PMID:Characterization of histamine-H3 receptors controlling non-adrenergic non-cholinergic contractions of the guinea-pig isolated ileum. 135 20

The structure of the gene encoding the bovine type B endothelin receptor (ETB) has been established and compared with those of other heptahelical receptors. The gene is present as a single copy in the bovine genome, as demonstrated by Southern blot analysis, and spans at least 36 kb. The coding region is divided into 7 exons separated by 6 introns, one of which is more than 23 kb in length. The exons correspond well to the structural domains of the receptor: the first exon encodes the first and second transmembrane domains, and each of the following transmembrane domains is encoded by a separate exon. The portion of the ETB protein sequence encoded by exon 3 is quite different from the corresponding ETA sequence, suggesting that this region is responsible for the distinct ligand specificities of the two receptor subtypes. The second intron interrupts the canonical Asp-Arg-Tyr sequence, which is located at the end of the third transmembrane domain of the heptahelical receptors, as with the substance P, substance K, dopamine D2 and dopamine D3 receptor genes. To map the 5' region of the gene and determine the start of transcription, primer-extended cDNAs were cloned and sequenced: multiple start sites were deduced with no apparent TATA box in the expected upstream region. Similar results were obtained by ribonuclease protection analysis.
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PMID:Structure of the bovine ETB endothelin receptor gene. 141 82

1. The classification of tachykinin receptors in the guinea-pig trachea has been investigated. This was of interest because, from previous studies, it was not clear whether the guinea-pig trachea contains either a mixture of NK1 and NK2 receptors or, alternatively, a single type of novel tachykinin receptor. 2. In the present study, the guinea-pig trachea was contracted by tachykinin agonists selective for NK1 receptors (substance P methylester (SPOMe) and GR73632) or NK2 receptors (GR64349) but not NK3 receptors (senktide). 3. Against SPOMe and GR73632, the NK1 antagonist, GR71251, behaved as a reversible competitive antagonist having apparent affinity (pKB 7.05 vs SPOMe) consistent with action at NK1 receptors. GR71251 (3 microM) did not antagonize responses to GR64349. 4. The NK2 antagonists L-659,877 and Ac-Leu-Asp-Gln-Trp-Phe-Gly-NH2 (R396) antagonized GR64349 although only R396 appeared to behave competitively (pKB 5.73). Neither L-659,877 (30 microM) nor R396 (30 microM) blocked responses to SPOMe. 5. For L-659,877 and R396, comparison was made between activity in guinea-pig trachea and in preparations known to contain tachykinin receptors predominantly of the NK2 type. In the rabbit trachea, both L-659,877 and R396 had effects similar to those in guinea-pig trachea. In contrast, in the rat colon muscularis mucosae, both L-659,877 and R396 appeared to behave competitively with pKB values against GR64349 of 7.83 and 6.90 respectively. 6. It is concluded that in guinea-pig trachea, contractile responses can be induced by activation of both NK1 and NK2 receptors. The present data are discussed with reference to the proposed existence of subtypes of the NK2 receptor.
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PMID:Receptors mediating tachykinin-induced contractile responses in guinea-pig trachea. 165 74


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