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)

The 3,5-bis(trifluoromethyl)benzyl ester of N-acetyl-L-tryptophan (3), which was derived from the screening lead N-ethyl-L-tryptophan benzyl ester, has been used as a starting point to identify high-affinity substance P receptor antagonists with improved in vivo activity. Altering the ester moiety to an amide or ether led to a substantial loss in binding affinity, but conversion to a ketone provided compounds with affinity comparable to the equivalent esters. A homochiral synthesis of the key intermediate amino ketone 15 was developed which allows its preparation on a large scale. From this intermediate a range of amine-containing acylamino derivatives were prepared with affinity optimized in the morpholinylbutyramide 161 which has an IC50 of 0.17 nM at the human NK1 receptor. In addition to improving affinity, the amino group also provided aqueous solubility for a number of these derivatives. When tested in vivo the quinuclidine derivative L-737,488 (16i) was found to be an orally active (ID50 = 1.8 mg/kg) inhibitor of substance P-induced dermal extravasation in the guinea pig.
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PMID:Synthesis and biological evaluation of NK1 antagonists derived from L-tryptophan. 753 62

We recently described a novel series of diacylpiperazine antagonists of the human neurokinin (NK)-1 receptor. The diacylpiperazine compounds are structurally dissimilar from previously described NK-1 antagonists. L-161,664 [1-(N,N-diphenylaminocarbonyl)-4-(N',N'-di-n-pentylaminocarbony l) piperazine-2-diethylaminopropylcarboxamide] inhibits 125I-substance P binding to the human NK-1 receptor with an IC50 of 43 +/- 21 nM but has 50-fold and 200-fold lower affinity for the human NK-2 and NK-3 receptors, respectively. L-161,664 inhibits substance P-stimulated inositol monophosphate accumulation in Chinese hamster ovary cells expressing the human NK-1 receptor by increasing the EC50 for substance P but not its maximal effect. The compound decreases the apparent affinity of the NK-1 receptor for 125I-substance P and does not alter the rate of dissociation of 125I-substance P from the receptor. These data indicate that L-161,664 is a potent and selective competitive antagonist of the human NK-1 receptor. L-161,664 has reduced affinity for mutants of the NK-1 receptor in which alanine has replaced Gln-165 in transmembrane helix 4, His-197 in helix 5, His-265 in helix 6, or Tyr-287 in helix 7. Similarly, a novel series of acyclic 2-benzhydryl-2-aminoethyl ethers that we have recently shown to be competitive NK-1 receptor antagonists have reduced affinity for the Q165A. H197A, and H265A mutant receptors. These residues have been shown to be important for binding of quinuclidine, tryptophan benzyl ester, and perhydroisoindole antagonists to the receptor. Analysis of the interaction of structural analogs of L-161,664 with the Q165A mutant receptor suggests that this residue interacts with the 2-diethylaminopropylcarboxamide side chain of L-161,664. Thus, even though the diacylpiperazine antagonists are structurally dissimilar from other classes of antagonists described to date, these data suggest that a common antagonist binding site that accomodates much structural diversity is present in the human NK-1 receptor. Furthermore, these data, combined with those obtained from medicinal chemistry approaches, suggest a minimum pharmacophore map for the interaction of these diverse ligands with the NK-1 binding site.
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PMID:Characterization of the interaction of diacylpiperazine antagonists with the human neurokinin-1 receptor: identification of a common binding site for structurally dissimilar antagonists. 753 86

A series of pseudopeptide analogs of the substance P-like hexapeptide Ava-Phe-Phe-Gly-Leu-Met-NH2 was produced by N alpha-protection, introduction of the thiomethylene bond, of D- and non-proteinogenic amino acids, and alteration of the side chain of tryptophan. Synthesis of the pseudopeptides on a solid phase was successfully improved by direct formation of the CH2-S bond on the resin. However, while thiomethylene formation between leucine and norleucine led to the expected SS diastereoisomer, the major product of the similar coupling between two phenylalanines was the SR isomer. An improved resistance of the analogs to proteolysis was observed, which could be related to the structural changes. Interestingly, these modifications led to three water-soluble and potent neurokinin antagonists on classical in vitro bioassays.
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PMID:Synthesis and in vitro activities of new tryptophan-modified and thiomethylene-containing pseudopeptide antagonists of the neurokinins. 822 84

We report on the synthesis and the pharmacological properties of a new series of tachykinin antagonists based on the pseudopeptide pharmacophore cyclo[-Abo-Asp(D-Trp-Phe-N(Me)Bzl)-] which contains the 2-azabicyclo[2.2.2]octane-3(S)-carboxylic acid (Abo) residue. Variation of the substituents on the tryptophan indole nitrogen was shown to modulate water solubility and transport properties of the analogs as well as potency in classical in vitro response and binding assays. One water-soluble compound, 16, in which the substituent was 3-carbonylpropionate, strongly prolonged the reaction time in the mouse hot-plate test both after iv or oral administration and was devoid of degranulating activity in rat peritoneal mast cells.
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PMID:Tetrapeptide tachykinin antagonists: synthesis and modulation of the physicochemical and pharmacological properties of a new series of partially cyclic analogs. 838 71

Early structure-activity studies on racemic tryptophan ester and amide NK-1 antagonists 5-7 led to the discovery that the potency of the series could be markedly increased by moving the carbonyl function in these molecules to an off-chain position as in the 3-aryl-1,2-diacetamidopropane 9. Further medicinal chemistry incorporating this change resulted in the discovery of a novel series of highly potent aryl amino acid derived NK-1 antagonists of the R stereoisomeric series (IC50's = 100 pM to > 5 microM). Compounds in this series were shown to be competitive antagonists using an in vitro NK-1 smooth muscle assay, and this data correlated well with observed human NK-1 binding affinities. Two of these agents, (R)-25 and (R)-32, blocked intrathecal NK-1 agonist-driven [Ac-[Arg6,Sar9,Met(O2)11]- substance P 6-11 (Ac-Sar9)] nociceptive behavior in mice. Both compounds potently blocked the neurogenic dural inflammation following trigeminal ganglion stimulation in the guinea pig after intravenous administration. Further, upon oral administration in this model, (R)-32 was observed to be very potent (ID50 = 91 ng/kg) and have a long duration of action (> 8 h at 1 micrograms/kg). Compound (R)-32, designated LY303870, is currently under clinical development as an NK-1 antagonist with a long duration of action.
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PMID:3-Aryl-1,2-diacetamidopropane derivatives as novel and potent NK-1 receptor antagonists. 857 17

In the present work we studied the interaction of alpha-MSH and substance P neuropeptides with gangliosides using lipid monolayers, fluorescence spectroscopy, and differential scanning calorimetry techniques. The positively charged weak amphiphilic neuropeptides did not show surface activity in the range of concentrations tested (0.1-0.3 muM), but they were preferentially able to penetrate monolayers formed by acidic lipids, showing the best interaction with the more complex gangliosides. The general order of interaction found for both peptides is GTIh > GDIa = GMI > DLPA > sulphatide. Neither neuropeptide interacted with phosphatidylcholine monolayers above 10 mN.m-1. The binding of alpha-MSH to GMI micelles followed by changes in the fluorescence of its tryptophan residue takes place with an increase in the hydrophobic environment of the neuropeptide. An apparent dissociation constant of 13 muM was estimated for this process. Similar result was found with GMI:DMPC vesicles (1:10 molar ratio). The thermotropic profile of GMI micelles is modified in the presence of the neuropeptides. The calorimetric enthalpy of GMI transition increased 21% and 37% in the presence of alpha-MSH and substance P, respectively. Both neuropeptides induced the same increment in the transition temperature Tm from 19 to 20.5 degrees C. The basic physicochemical studies herein indicated that both positively charged neuropeptides, alpha-MSH and substance P, interact with interfaces containing gangliosides in a mainly electrostatic form, whereas the hydrophobic interaction seems to play a secondary role.
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PMID:Interaction of alpha-MSH and substance P with interfaces containing gangliosides. 880 33

A study of structure-activity relationships of a series of L-tryptophan derivative NK-1 antagonist was performed using 3,5-bis(trifluoromethyl)benzyl ester of N-acetyl-L-Tryptophan (IV) as a starting point. The ester moiety was replaced with several amidic functions while the N-acetyl group (Ac-) was retained (compounds 1-8) or changed into a benzyloxycarbonyl group (Z-) (compounds 9-16). The compounds were tested on guinea pig ileum longitudinal muscle, rat colon muscolaris mucosae, and rat everted portal vein, representative of tachykinin NK-1, NK-2 and NK-3 receptors, respectively. Both, Ac- and Z-series showed generally moderate antagonist activity on tachykinin NK-1 receptors with respect to the reference drug IV. The most potent term was compound 2 (Ac-Trp-N(CH3)CH(CH3)Ph with S-configuration at the C-terminus) which exhibited pA2 values of 7.0, 4.2 and 4.4 on NK-1, NK-2 and NK-3 sites, respectively.
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PMID:Synthesis and in vitro activities of NK-1 antagonists derived from L-tryptophan. 950 70

We have investigated the contractile property of cyclosporin A and FK506 in guinea-pig isolated bronchus. Cyclosporin A (10 microM) failed to significantly attenuate the excitatory non-adrenergic non-cholinergic (eNANC) and cholinergic contractile response (per cent methacholine Emax) induced by electrical field stimulation (EFS). In contrast, eNANC responses were significantly attenuated by both the neurokinin (NK)-1 and (NK)-2 receptor antagonists, N-acetyl-L-tryptophan 3,5-bis (trifluoromethyl)-benzyl and SR48968, respectively. Cyclosporin A and FK506 caused a concentration-dependent contraction in guinea-pig isolated bronchus, which was significantly attenuated by NK-1 and NK-2 receptor antagonists. The capsaicin receptor antagonist, capsazepine (10 microM) significantly reduced the contractile response to cyclosporin A and capsaicin, but not to FK506. The N-type calcium channel blocker, omega-Conotoxin (omegaCTX: 10 nM), significantly reduced the contractile response to FK506 and the eNANC response following EFS. In contrast, omega-CTX failed to significantly reduce the contractile potency to capsaicin or cyclosporin A. In bronchial preparations desensitized by repeated application of capsaicin (1 microM), the contractile responses to both cyclosporin A (100 microM) and FK506 (100 microM), were significantly reduced. In contrast, the contractile responses to substance P and neurokinin A (10 microM) were not altered. Furthermore, repeated application of cyclosporin A (100 microM) significantly inhibited the contractile response to capsaicin (1 microM). The findings from this study would indicate that cyclosporin A and FK506 mediate contraction of guinea-pig isolated bronchus secondary to the release of neuropeptides from airway sensory nerves. However, the release of sensory neuropeptides appears to be mediated via different mechanisms for cyclosporin A and FK506, the former by stimulation of the vanilloid receptor and the latter via opening of N-type calcium channels.
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PMID:Stimulation of airway sensory nerves by cyclosporin A and FK506 in guinea-pig isolated bronchus. 988 67

The serotonergic system has repeatedly been discussed to be involved in the pathophysiology of fibromyalgia (FM), which is a syndrome of widespread pain and sleep disturbance. Elevated levels of substance P (SP), a mediator of nociception, have been described in FM. In this study the possible relationship between SP and serotonin (5-HT) together with its precursor tryptophan (TRP) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) was evaluated in 51 serum samples of fibromyalgia patients. These parameters were compared with clinical data such as pain intensity or sleep quality. A strong negative correlation between SP and 5-HIAA (P = .000) as well as between SP and TRP (P = .009) could be demonstrated. High serum concentrations of 5-HIAA and TRP showed a significant relation to low pain scores (5-HIAA: P = .030; TRP: P = .014). Moreover, 5-HIAA was strongly related to good quality of sleep (P = .000), while SP was related to sleep disturbance (P = .005). These data are valid to support the hypothesis of a systemic involvement of 5-HT and SP in fibromyalgia.
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PMID:Relationship of substance P, 5-hydroxyindole acetic acid and tryptophan in serum of fibromyalgia patients. 1002 91

The brains of two patients with Lesch-Nyhan syndrome (LNS) were studied. The concentration of dopamine was decreased in the caudate nucleus of LNS patients. Immunohistochemical methods revealed that the dopamine (DA) D1 and D2 receptor and methionine-enkephalin immunoreactivities (IRs) were increased in the putamen, and less significantly in the caudate nucleus. The D1 and D2 receptor IRs of the cingulate cortex, the tryptophan-hydroxylase IR in the dorsal nucleus of the midbrain, as well as the substance P and methionine-enkephalin IRs of the nociception-conducting structures, including the periaqueductal gray and spinal trigeminal nucleus, were not changed. Tyrosine-hydroxylase IR was not decreased in the substantia nigra of the LNS patients. Therefore, the cause of the decreased dopaminergic activity in LNS may not be involved in the production of tyrosine hydroxylase in the substantia nigra. Developmental abnormalities due to the DA defect at an early age might exist in the postsynaptic structure in the striatum.
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PMID:Dopamine receptor upregulation in Lesch-Nyhan syndrome: a postmortem study. 1040 87


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