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)

Structural considerations led us to postulate that the introduction of the dipeptides DPro9-Pro10 and DPro9-MeLeu10 should lock the C-terminal tetrapeptide of SP in a type II' beta-turn structure, a prerequisite for antagonist activity. Indeed, as the GR 71251, [DPro9, Pro10, Trp11]SP was more potent in inhibiting the septide, (pA2 = 6.5), than the [Pro9]SP, (pA2 < or = 5), spasmogenic activity in the guinea-pig ileum bioassay. This result confirms that septide, [pGlu6, Pro9]SP(6-11), a peptide active in the guinea-pig ileum bioassay and practically devoid of binding potencies for the three specific NK-1, NK-2 and NK-3 tachykinin binding sites interacts with a tachykinin receptor different from the NK-1 receptor sensitive to [Pro9]SP. Interestingly enough, the reintroduction of the leucine side-chain in position 10 yielded [DPro9, MeLeu10, Trp11]SP, an antagonist, equipotent in inhibiting both the septide- and the [Pro9]SP-evoked contractile response in the guinea-pig ileum bioassay, (pA2 = 6.6).
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PMID:[Pro9]SP and [pGlu6, Pro9]SP(6-11) interact with two different receptors in the guinea-pig ileum as demonstrated with new SP antagonists. 128 Jul 87

[Pro9]SP and septide have been described as selective agonists for the SP receptor (NK-1 type). These two peptides contract with a great efficacy the guinea-pig ileum, but unexpectedly septide was practically devoid of affinity for the NK-1 site labelled by 3H-[Pro9]SP. Like septide, SP analogues like SP-O-CH3, [Apa9-10]SP and [Pro9,10]SP share the same peculiar properties. In addition, the contracting activity of these peptides is not explained by an interaction with NK-2 or NK-3 sites. GR 71,251, a compound which has been described as NK-1 antagonist, was more potent in inhibiting the septide- and the [Apa9-10]SP- than the [Pro9]SP-evoked contracting responses. Altogether, these results suggest that septide, SP-O-CH3, [Apa9-10]SP and [Pro9,10]SP exert their high contracting activity in the guinea-pig ileum by acting on a new type of tachykinin receptor.
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PMID:[A new tachykinin receptor revealed by substance P analogues in the guinea pig ileum]. 128 14

The possible existence of NK-2 receptor subtypes in peripheral smooth muscle preparations from rabbit and hamster was investigated by studying the effect of neurokinin A, the selective NK-2 receptor agonist [beta Ala8] neurokinin A (4-10), the selective NK-2 tachykinin receptor antagonists, MEN 10,376, L 659,877 and R 396, and the pseudopeptide derivative of neurokinin A (4-10), MDL 28,564. All experiments were performed in the presence of peptidase inhibitors (captopril, bestatin and thiorphan, 1 microM each). Both neurokinin A and [beta Ala8] neurokinin A (4-10) produced concentration-dependent contractions of the rabbit isolated bronchus and hamster isolated stomach and colon, as well as enhancement of the nerve-mediated twitches of rabbit isolated vas deferens (pars prostatica). MEN 10,376, L 659,877 and R 396 antagonized the effect of the NK-2 receptor selective agonist in all four tissues under study, although marked differences in antagonist potency were evident for the three antagonists. Thus MEN 10,376 was distinctly more potent (about 100 times) in rabbit than in hamster preparations while L 659,877 and R 396 were more potent in hamster than rabbit preparations. MDL 28,564 showed a distinct agonist character in rabbit preparations while it was virtually inactive in hamster preparations, where it antagonized the effect of the NK-2 receptor selective agonist.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Heterogeneity of NK-2 tachykinin receptors in hamster and rabbit smooth muscles. 131 59

Substance P is a member of a family of structurally related peptides, called tachykinins, that are involved in the regulation of many biologic processes. Diversity in the generation of multiple tachykinin peptides arises due to multiple genes encoding these peptides as well as by mechanisms of alternative RNA processing and differential posttranslational processing. The multiple peptides are neurotransmitters and/or neuromodulator substances, and they bring about their actions mainly by activating three primary types of receptors, NK-1, NK-2, and NK-3. The pharmacology and tissue locations of these receptor sites are discussed, as is their involvement in certain biologic responses. These three receptor sites have been molecularly characterized by cDNA cloning and functional expression, and all are members of the superfamily of receptors coupled to G-regulatory proteins. Second messenger systems established to be activated by tachykinin receptor stimulation include the hydrolysis of inositol containing phospholipids by a phospholipase C mechanism. The role of substance P in neurogenic inflammation and plasma extravasation is briefly discussed. The generation of new research tools recently in the tachykinin field should allow for a detailed examination of the mechanisms of peptide action, including a focus on receptor structure-function relations and regulation of receptor sensitivity.
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PMID:Structure, functions, and mechanisms of substance P receptor action. 131 25

The effects of intradermal injection of CP-96,345 and Men 10207, selective antagonists for NK-1 and NK-2 tachykinin receptors, respectively, on the extravasation of plasma protein induced by antidromic stimulation of unmyelinated sensory fibers in the sciatic nerve was studied in rat hindpaw. Activation of unmyelinated fibers by antidromic sciatic nerve stimulation (1 Hz, 5 min) consistently evoked a localized plasma extravasation of Evans blue on the skin area of the hindpaw innervated by the sciatic nerve, which was not inhibited by intradermal injection of saline or Men 10207 (9 and 35 nmol). In contrast, CP-96,345 (3 and 9 nmol, but not 1 nmol), injected intradermally 15 min prior to nerve stimulation dose-dependently inhibited this response. Plasma extravasation induced by intravenously injected substance P was also inhibited by CP-96,345. Since CP-96,345 is a highly selective antagonist for NK-1 tachykinin receptors, it is suggested that the plasma extravasation induced by antidromic C-fiber stimulation and by systemically applied tachykinins is mediated by NK-1 tachykinin receptors.
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PMID:NK-1, but not NK-2, tachykinin receptors mediate plasma extravasation induced by antidromic C-fiber stimulation in rat hindpaw: demonstrated with the NK-1 antagonist CP-96,345 and the NK-2 antagonist Men 10207. 131 17

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

Incorporation of D-Pro9 into substance P related peptides is known to enhance neurokinin NK-2 receptor agonist potency and selectivity with respect to other neurokinin receptors. We now report that replacement of D-Trp9 by D-Pro9 in the nonselective neurokinin antagonist [Arg5,D-Trp7,9, Nle11]-SP(5-11) gave a partial agonist with NK-2 receptor selectivity. Further incorporation of Pro10 provided the weak but selective NK-2 antagonist Arg-Ala-D-Trp-Phe-D-Pro-Pro-Nle-NH2 (compound 4; NK-2 pKB = 5.9; NK-1 pKB = 4.7; NK-3 pKB less than 4.6). Addition of a suitable lipophilic N-terminal substituent (e.g. Boc, PhCO, cyclohexylcarbonyl) to this compound greatly enhanced NK-2 antagonist activity (compound 10, GR 83074; NK-2 pKB = 8.2), and combined with further optimization of the N-terminal amino acids, provided the extremely potent and selective NK-2 antagonist PhCO-Ala-Ala-D-Trp-Phe-D-Pro-Pro-Nle-NH2 (compound 34, GR 94800; NK-2 pKB = 9.6; NK-1 pKB = 6.4; NK-3 pKB = 6.0). Compounds of this class produced a potent inhibition of NK-2 agonist-induced bronchoconstriction in the anaesthetized guinea-pig.
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PMID:Highly potent and selective heptapeptide antagonists of the neurokinin NK-2 receptor. 132 7

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

Polymerase chain reaction was applied to human genomic DNA using primers corresponding to the rat substance P receptor cDNA. As a result, a fragment of 94 b.p. was isolated identical to the fragment 771-864 of the above-mentioned cDNA, with the exception of the G796----A substitution (Val----Ile in the amino acid sequence). A comparison of the established sequence with the published structures of tachykinin receptors of NK-1, NK-2 and NK-3 types allows its assignment to the substance P receptor (NK-1 tachykinin receptor) gene detected in the human genome.
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PMID:[Identification of a segment of the gene for the substance B receptor in the human DNA genome using the polymerase chain reaction]. 132 71

The design and synthesis of potent and selective neurokinin NK-2 receptor agonists 12 (GR64349) and 31 are described, together with structure-activity relationships for related analogues. Compound 12 (EC50 = 3.7 nM at NK-2 receptors in the rat colon; selectivity > 1000- and > 300-fold with respect to NK-1 and NK-3 receptors, respectively) was derived by incorporation of a Gly-Leu gamma-lactam conformational constraint into the C-terminal region of the neurokinin A octapeptide analogue [Lys3]-NKA(3-10). Compound 31 (EC50 = 15 nM in rat colon) contains a novel fused-bicyclic constraint at the corresponding site in the substance P hexapeptide analogue [Ava6]-SP(6-11).
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PMID:Conformationally constrained tachykinin analogues: potent and highly selective neurokinin NK-2 receptor agonists. 133 60


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