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)

beta-Amyloid (1-40) and (25-35) have been reported to be toxic to primary cultured neurons. beta-Amyloid (1-40) was also reported to induce neurodegeneration following intracerebral injection. We attempted to replicate and extend these findings by injecting both the full length amyloid peptide and the 25-35 fragment. beta 1-40 (3 nmol in 1 microliter) or beta 25-35 (20 nmol in 2 microliters) in a vehicle of 10% DMSO (3 and 10 mM concentration, respectively) induced tissue loss and neurodegeneration. We also attempted to prevent the amyloid-induced damage by coinjecting 200 nmol of Substance P. There was no obvious reduction in the size of the lesions. Other studies, however, have reported antagonism of amyloid toxicity with tachykinin agonists. Since beta-amyloid does not appear to bind to tachykinin receptors, there is some question as to the site of the putative interaction of these peptides and, therefore, the mechanism by which beta-amyloid induces tissue damage. Our own results and published cell culture toxicity studies suggest that aggregation of the peptide and physical displacement of tissue may be responsible for both the neuronal and tissue loss, although this hypothesis is not consistent with other published findings.
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PMID:Intracerebral beta-amyloid(25-35) produces tissue damage: is it neurotoxic? 128 Dec 89

The cryoprotective effect of sucrose has been investigated using 3 different vascular smooth muscle preparations, namely canine saphenous veins and arteries and porcine circumflex coronary arteries following storage in liquid nitrogen (at -196 degrees C). Contractile responses to noradrenaline, 5-HT, prostaglandin F2 alpha and KCl and relaxant responses to substance P and 5-HT were determined on fresh tissues and after cryostorage in fetal calf serum (FCS) containing either 1.8 M dimethyl sulfoxide (DMSO), or 0.1 M sucrose or both agents combined. The data demonstrate that the addition of sucrose to the DMSO-containing cryomedium promotes the preservation of both contractile and relaxant activity of cryostored blood vessels, though sucrose alone did not confer any noticeable protection.
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PMID:Sucrose promotes the functional activity of blood vessels after cryopreservation in DMSO-containing fetal calf serum. 152 75

NKA (4-10), the C-terminal heptapeptide fragment (Asp-Ser-Phe-Val-Gly-Leu-Met-NH2) of tachykinin NKA, is more active than the parent native compound in the interaction with the NK-2 receptor. Substitution of Gly8 with the more flexible residue beta-Ala8 increases its selectivity with respect to other two known receptors (NK-1 and NK-3), whereas substitution with either D-Ala8 or GABA8 deprives the peptide of its biological activity. These findings can be interpreted by a conformational analysis based on NMR studies in DMSO-d6 and in a DMSO-d6/H2O cryoprotective mixture combined with internal energy calculations. NKA(4-10) is characterized by a structure containing a type I beta-turn extending from Ser5 to Gly8, followed by a gamma-turn centered on Gly8, whereas for [beta-Ala8]NKA(4-10) is possible to suggest a type I beta-turn extending from Ser5 to beta-Ala8, followed by a C8 turn comprising beta-Ala8 and Leu9 and by another beta-turn extending from beta-Ala8 to the terminal NH2. The preferred conformation of [beta-Ala8]NKA(4-10) is not compatible with models for NK-1 and NK-3 agonists proposed on the basis of rigid peptide agonists [Levian-Teitelbaum et al. (1989) Biopolymers 28, 51-64; Sumner & Ferretti (1989) FEBS Lett. 253, 117-120]. The preferred solution conformation of [beta-Ala8]NKA(4-10) may thus be considered as a likely bioactive conformation for NK-2 selective peptides.
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PMID:Conformation-activity relationship of tachykinin neurokinin A (4-10) and of some [Xaa8] analogues. 165 41

The substituted glucopyranose ring structure 2-hydroxypropyl-beta-cyclodextrin (CDEX) increases the solubility of molecules by inclusion of the agent in the lipophilic interior of the ring. This property is of particular use for the administration of molecules by the intracerebral (ICV) or intrathecal (IT) routes. In concentrations up to 40% w/v (isotonic), this agent (10 microliters) effect upon nociceptive or motor function after IT injection or on EEG and general behavior after ICV injection in rats. Using 20% CDEX, there is no change in the ED50 as compared to saline on the hot plate (HP) after IT injection of morphine, D-Ala2-D-Leu5 enkephalin or Tyr-Aib-Gly-gPhe-mAib-NH2, (Aib: alpha-aminoisobutyric acid) although there is an increase in their respective durations of effect. Cyclic peptide opioids: Tyr-c[D-A2bu-Gly-D-beta Nal(1)-D-Leu] (A2bu: alpha, gamma-diaminobutyric acid; beta-Nal(1): beta-naphthylalanine(1)) or Tyr-c[DA2bu-Gly-beta Nal(1)-D-Leu] are insoluble in saline but are readily dissolved in CDEX, and display a naloxone-sensitive antinociception following spinal administration. In other studies, saline insoluble capsaicin is administered in 25% dimethylsulfoxide (DMSO) or 20% CDEX (15 microliters; 5 mg/ml) which result in a significant reduction in the spinal levels of substance P and calcitonin gene related peptide and an increase in the HP latency. DMSO alone, but not CDEX alone, reduces the levels of the two peptides. These data emphasize the utility of complexation with CDEX for intracerebral drug delivery and compatibility with brain and spinal tissue.
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PMID:The utility of 2-hydroxypropyl-beta-cyclodextrin as a vehicle for the intracerebral and intrathecal administration of drugs. 170 20

Two new cyclic analogues of physalaemin were designed on the basis of the conformation found in DMSO solution. Glp-Ala-cyclo(-Asp-Pro-Asn-Lys-)-Phe-Tyr-Gly-Leu-Met-NH2 (1) was synthesized by cyclization of physalaemin. In 2 the Asp residue was replaced by Glu. The linear analogue of 2 was synthesized by the solid phase method and subsequently cyclized. Two-dimensional nmr methods were employed to assign the proton and carbon resonances. Proton-proton distances were extracted from rotating frame nuclear Overhauser effect spectra and used as restraints in the molecular dynamics calculations. Analogue 1 was found to have a similar conformation as physalaemin, whereas 2 did not form intramolecular hydrogen bonds. The pharmacological evaluation revealed that both peptides have similar potencies as physalaemin in the dog carotid artery (NK-1 receptor). Therefore, the charged side chains of physalaemin appear not essential for NK-1 activation. However, the other tachykinin receptors show good sensitivity to the cyclic peptides. It is concluded that the replacement of a salt bridge by an amide bond connecting the side chains of natural residues might provide useful information about the biological significance of some charged side chains of neurokinins.
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PMID:Conformation-based design of two cyclic physalaemin analogues. 193 67

Proton nmr parameters are reported for DMSO-d6 solutions of two receptor-selective substance P analogues: Ac[Arg6,Pro9]SP6-11, which is selective for the NK-1 (SP-P) receptor and [pGlu6,N-MePhe8]SP6-11, which selectively activates the NK-3 (SP-N) receptor. Full peak assignments of both analogues were obtained by COSY experiments. The chemical shifts, coupling constants, and temperature coefficients of amide proton chemical shifts as well as NOESY effects and calculated side-chain rotamer populations of Phe side chains are reported for both peptides. Analysis of coupling constants and temperature coefficients together with the nuclear Overhauser enhancement spectroscopy effects suggest that Ac[Arg6,Pro9]SP6-11 has a trans configuration about the Phe8-Pro9 amide bond and the preferred conformation of this analogue has a type I beta-turn. The nmr data for [pGlu6,N-MePhe8]SP6-11 suggest that this peptide exists as a mixture of cis-trans isomers in which the cis isomer can preferably adopt a type VI beta-turn conformation, and the trans isomer can adopt a gamma-turn conformation. There are indications that the two last turns are stabilized by a hydrogen bond between the syn carboxamide proton and the pGlu ring carbonyl.
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PMID:1H-NMR studies of receptor-selective substance P analogues reveal distinct predominant conformations in DMSO-d6. 247 Apr 38

High-resolution proton spectra at 500 MHz of two tachykinin peptides, substance P methyl ester (SPOMe) and [Nle10]-neurokinin A (4-10), have been obtained in dimethylsulfoxide (DMSO), and for SPOMe, also in 2,2,2-trifluoroethanol (TFE)/water mixtures. Complete chemical shift assignments for these peptides were made based on two-dimensional (2D) nmr techniques, correlated spectroscopy and total COSY. J coupling measurement and nuclear Overhauser effect spectroscopy (NOESY) were then used to determine the conformation of these peptides in the various solvents. Based on the J coupling, NOE correlations, and temperature coefficients of the NH resonances, it is concluded that these two peptides exist in DMSO at room temperature as a mixture of conformers that are primarily extended. For SPOMe in TFE/water with high TFE content, however, helical structures are found to be present, and they become quite clear at temperatures between 270 and 280 K. The variation of the 13C chemical shifts of the C alpha (the secondary shift) with TFE contents corroborates this conclusion. The NOE and C alpha shifts show that the main helical region for SPOMe lies between 4P and 9G. The C-terminus segment L-M-NH2 is found to be quite flexible, which appears to be quite common for neurokinin-1 selective peptides.
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PMID:Solution conformation study of substance P methyl ester and [Nle10]-neurokinin A (4-10) by NMR spectroscopy. 750 36

The conformations of two backbone-cyclized substance P analogs as derived from 1H NMR and molecular dynamics simulations carried out in DMSO and water are described. The method of floating chiralities is used in the simulations to facilitate the diastereotopic assignment of methylene protons. One of the analogs, cyclo-[-(CH2)3-NH-CO-(CH2)4-Arg-Phe-Phe-N-]-CH2-CO-Leu-Met-NH2, is a highly active, selective agonist for the NK-receptor, while the other, cyclo[-(CH2)2-NH-CO-(CH2)2-Gly-Arg-Phe-Phe-N-]-CH2-CO-Leu-Met-NH2, is inactive. Both analogs contain cyclic ring systems of the same size, varying in only the number of amide linkages. From the conformational analysis, the lack of activity can be attributed to the introduction of too much constraint into the ring system. This has an effect on the topological array of the important residues Arg-Phe-Phe. The results presented here are compared with biologically active analogs previously examined. The differences between conformations of active and inactive compounds are used to develop insight into the conformational requirements for biological activity.
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PMID:Comparison of the conformation of active and nonactive backbone cyclic analogs of substance P as a tool to elucidate features of the bioactive conformation: NMR and molecular dynamics in DMSO and water. 751 22

A highly potent and selective agonist to the tachykinin NK-3 receptor, [pGlu6,N-MePhe8,Aib9] substance P (6-11) (I), was synthesized via the solid phase method. The ED50 of I was 4 nM in the guinea pig ileum in the absence of atropine (NK-1+NK-3 receptors) and this agonist was 5000-fold less potent in the presence of atropine (NK-1 receptor). The analogue was virtually inactive in the rat vas deferens (NK-2 receptor). A detailed analysis of the solution conformation of this analogue in DMSO-d6 and in a DMSO-d6/H2O cryomixture was carried out by a combination of 1H-nmr 2D techniques (DQF-COSY, TOCSY, NOESY and ROESY) and model building based on empirical energy calculations. Peptide I exists as a mixture of isomers containing cis and trans Phe-N-MePhe peptide bonds. The main isomer, containing a cis Phe-N-MePhe peptide bond, shows a preferred folded conformation characterized by a type VI beta-turn with Phe and N-MePhe in the i + 1 and i + 2 positions. The turn is followed by a helical segment extending to the C-terminal. This conformation is compared to previously reported conformations of other selective tachykinin agonists and may be a promising lead for the design of novel NK-3 agonists with additional conformational constraints.
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PMID:Synthesis, biological activity, and conformational analysis of [pGlu6,N-MePhe8,Aib9] substance P (6-11): a selective agonist for the NK-3 receptor. 768 10

The conformation of cyclo-[Gln-Trp-Phe-Gly-Leu-Met], a potent tachykinin antagonist selective for the NK-2 receptor, has been studied by 1H NMR spectroscopy in DMSO-d6 and in a DMSO-d6/H2O cryoprotective mixture in the temperature range 280-320 K. The NMR data cannot be interpreted on the basis of a single ordered conformation. An exhaustive search, based mainly on missing NOEs among skeleton protons, yields a description of the conformational state in solution consisting of a few interconverting structures that can explain all observed NMR parameters. The relative position of the side chains of key residues may be interpreted in terms of bioactive conformations.
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PMID:Solution conformation of c-[Gln-Trp-Phe-Gly-Leu-Met], a NK-2 tachykinin antagonist. 770 77


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