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1.
Carmen Mrestani-Klaus Wolfgang Brandt Ralf Schmidt Klaus Neubert Peter W. Schiller 《Archiv der Pharmazie》1996,329(3):133-142
A conformational study of the cyclic β-casomorphin-5 analogues H-Tyr-cyclo[-D-Orn-2-Nal-Pro-Gly-] ( 1 ) (μ-selective agonist; 2-Nal = 2-naphthylalanine), H-Tyr-cyclo[-D-Orn-2-Nal-D-Pro-Gly-] ( 2 ) (mixed μ agonist/δ antagonist) and H-Tyr-cyclo[-D-Orn-Phe-D-Pro-Gly-] ( 3 ) (highly potent μ and δ agonist) has been carried out using 1H NMR spectroscopy. A complete assignment of the proton resonances of the three pentapeptides has been achieved. Compound 1 was shown to exist in two conformations, a major one (90%) characterized by a cis amide bond between 2-Nal3 and Pro4, and a minor one (10%) showing cis amide bonds both between D-Orn2 and 2-Nal3 and between 2-Nal3 and Pro4. Peptides 2 and 3 each showed only one conformer with all-trans peptide bonds in both cases. Temperature dependence studies of the amide proton chemical shifts indicated the existence of several intramolecular hydrogen bonds in the case of compounds 2 and 3 but not in the case of peptide 1. The backbone conformations of 2 and 3 were found to be similar, both being characterized by two consecutive γ turns around the D-Pro4 and D-Orn2 residues, respectively, and by a D-Orn2-CO←HNδ-D-Orn2 hydrogen bond. Altogether, the overall backbone conformation and the preferred side chain conformation were found to be roughly similar for the three title peptides. For all three compounds a close proximity between the aromatic moiety of the 3-position residue (2-Nal or Phe) and the D(or L)-Pro4 residue was established on the basis of ROESY experiments. The examination of low energy conformations obtained in molecular modelling studies by taking into account the various experimentally found NMR parameters (NOEs, vicinal H,H coupling constants, torsion angles, H-bonds) led to proposals of the solution conformation for each peptide. These conformations are in close agreement with a pharmacophore model for μ opioid receptor binding compounds. 相似文献
2.
Pauline L. Martin Thomas W. Gero Alice Anne Potts Noel J. Cusack 《Drug development research》1995,36(4):153-165
Structure-activity studies using naphthylmethyl analogs of β, γ-methylene-ATP were conducted at the P2X-purinoceptor that mediates contraction of the rabbit ear central artery by ATP, α, β-m-ATP. On the adenine base, substitution at the C2-position (WRC-0440) increased the agonist potency 2-fold and substitution at the C8-position (WRC-0431) did not change agonist potency, and both compounds had the same maximal response as β, γ-m-ATP, whereas substitution at the N6-position (WRC-0416) abolished activity. On the D-ribose sugar, substitution on the 2′-hydroxyl generated a partial agonist (WRC-0479), which had a maximal effect of only 39% of that of β-γ-m-ATP. Attempts to substitute the 3′-hydroxyls by naphthylmethyl failed, but substitution by p-methoxybenzyl (WRC-0617) did not change potency or the maximal response. Cyclic substitution of both the 2′- and 3′-hydroxyls by naphthylmethylidine (WRC-0498) had no effect on the agonist potency or the maximal response relative to β-γ-m-ATP. On the β, γ-methylenetriphosphonate chain, substitution on the methylene linkage by naphthylmethyl (WRC-0433) had no effect on agonist potency, but the maximal response increased to 122% that of β-γ-ATP. However, the contractile response to WRC-0433 was not desensitized by α, β-γ-ATP (contractile responses to all other agonists were abolished by α-β-γ-ATP pretreatment), but was blocked by the α1 antagonist prazosin (10?6 M). WRC-0433 appears to act at a prejunctional site that mediates ATP-induced release of norepinephrine. Purine nucleotides with substituents at the 2′-position of the ribose sugar could provide a lead to the generation of P2X-purinoceptor antagonists. © 1995 Wiley-Liss, Inc. 相似文献
3.
We report the synthesis and binding properties of specific photoaffinity ligands for μ and δ opioid receptor subtypes. These ligands are derived from DAGO: Tyr-D-Ala-Gly-NMePhe-Gly-ol, a μ selective probe and DTLET: Tyr-D-Thr-Gly-Phe-Leu-Thr, a δ selective probe by modifying the Phe 4 residue. These modifications are: i) a nitro group on the para position of Phe ring as Phe(4 NO2) or Nip, ii) an azido group as Phe(4 N3) or AZ. Pharmacological responses on mouse vas deferens (δ sites) and guinea pig ileum (μ sites), as well as competition experiments with [3H] DAGO and [3H] DTLET on crude rat brain membranes have been performed. The nitro group on the phenyl ring of the Phe residue preserves the affinity and selectivity of each probe: NipDAGO for the μ sites, NipDTLET for the δ ones. However the nitro probes do not appear to be photo-activable by u.v. irradiation. Likewise, azidation of the phenyl ring of the Phe residue does not change the receptor selectivity of each probe, but AZDAGO has less affinity than its parent molecule DAGO, while AZDTLET has more affinity than DTLET. These compounds are photoactivable and provide an efficient tool to characterize and isolate the different receptor subtypes, especially the δ site. 相似文献
4.
Abstract: New analogues of deltorphin I (DT I), in which the Phe residue in position 3, and the Val residue in position 5 or 6 are replaced with respective amphiphilic α‐hydroxymethylamino acid residues (HmAA), were synthesized and tested for receptor affinity and selectivity to μ and δ opioid receptors. The analogue with (R)‐HmPhe at position 3 lost receptor selectivity, as a result of a partial decrease of affinity to δ and a significant increase of affinity to μ receptors. In contrast, an analogue with (S)‐HmPhe in the same position, was very potent and more specific to δ receptors than parent DT I. The analogue with (R)‐HmVal at position 5 expressed higher δ affinity and selectivity than parent DT I. The analogue with other possible isomer (S)‐HmVal was less selective for δ opioid receptors, as a result of decreasing affinity to δ and increasing affinity to μ receptors. The analogues with (R)‐ or (S)‐HmVal in position 6 expressed equally low receptor affinity and selectivity. The data obtained support a previously proposed model of active conformation of deltorphins. 相似文献
5.
Abstract: There is evidence to indicate that opioid compounds with mixed μ agonist/δ antagonist properties are analgesics with low propensity to produce tolerance and physical dependence. A chimeric peptide containing the potent and selective μ agonist H‐Dmt‐D‐Arg‐Phe‐Lys‐NH2 ([Dmt1]DALDA) (Dmt = 2′,6′‐dimethyltyrosine) and the potent and selective δ antagonist H‐Tyr‐TicΨ[CH2‐NH]Cha‐Phe‐OH (TICP[Ψ]) (Cha = cyclohexylalanine), connected ‘tail‐to‐tail’ via a short linker, was synthesized using a combination of solid‐phase and solution techniques. The resulting peptide, H‐Dmt→D‐Arg→Phe→Lys‐NH‐CH2‐CH2‐NH‐Phe←Cha[NH‐CH2]ΨTic←Tyr‐H, showed the expected μ agonist/δ antagonist profile in the guinea‐pig ileum and mouse vas deferens assays. Its μ and δ receptor binding affinities were in the low nanomolar range, as determined in rat brain membrane binding assays. 相似文献
6.
Oliwia Frączak Anika Lasota Anna Leśniak Andrzej W. Lipkowski Aleksandra Olma 《Chemical biology & drug design》2014,84(2):199-205
Biphalin, a synthetic opioid peptide with a broad affinity for all opioid receptors (δ, μ, and κ) and high antinociceptive activity, has been under extensive study as a potential analgesic drug. This study presents the synthesis and biological properties of four new analogues of biphalin containing amphiphilic α‐alkylserines in position 2 and 2′. The incorporation of bulky α,α‐disubstituted amino acids in the peptide chain using standard peptide chemistry is often unsuccessful. We synthesized depsipeptides, and then, the desired peptides were obtained by internal O,N‐migration of the acyl residue from the hydroxyl to the amino group under mild basic conditions. The potency and selectivity of the new analogues were evaluated by a competitive receptor‐binding assay in the rat brain using [3H]DAMGO (a μ ligand) and [3H]DELT (a δ ligand). Their binding affinity is strongly dependent on the chirality of α‐alkylserine, as analogues containing (R)‐α‐alkylserines displayed higher μ receptor affinity and selectivity than those incorporating the (S)‐isomers. 相似文献
7.
EWA CISZAK GRZEGORZ PIETRZY
SKI BARBARA RZESZOTARSKA 《Chemical biology & drug design》1992,39(3):218-222
The crystal structure of Ac-Pro-ΔVal-NHCH3 was examined to determine the influence of the α,β-dehydrovaline residue on the nature of peptide conformation. The peptide crystallizes from methanol-diethyl ether solution at 4° in needle-shaped form in orthorhombic space group P212121 with a= 11.384(2) Å, b = 13.277(2) Å, c = 9.942(1) Å. V = 1502.7(4) Å3 Z = 4, Dm= 1.17 g cm?3 and Dc=1.18 g cm?3 The structure was solved by direct methods using SHELXS-86 and refined to an R value of 0.057 for 1922 observed reflections. The peptide is found to adopt a β-bend between the type I and the type III conformation with φ1=?68.3(4)°, ψ1=? 20.1(4)°, φ2=?73.5(4)°= and Ψ2=?14.1(4)°=. An intramolecular hydrogen bond between the carbonyl oxygen of ith residue and the NH of (i+ 3)th residue stabilizes the β-bend. An additional intermolecular N.,.O hydrogen bond joins molecules into infinite chains. In the literature described crystal structures of peptides having a single α,β-dehydroamino acid residue in the (i+ 2) position and forming a β-bend reveal a type II conformation. 相似文献
8.
S. Liao M. Shenderovich Z. Zhang V.J. Hruby K.E. Kvr K. Hosohata P. Davis F. Porreca H.I. Yamamura 《Chemical biology & drug design》2001,57(4):257-276
Abstract: Replacement of Phe3 in the endogenous δ‐opioid selective peptide deltorphin I with four optically pure stereoisomers of the topographically constrained, highly hydrophobic novel amino acid β‐isopropylphenylalanine (β‐iPrPhe) produced four pharmacologically different deltorphin I peptidomimetics. Radiolabeled ligand‐binding assays and in vitro biological evaluation indicate that the stereoconfiguration of the iPrPhe residue plays a crucial role in determining the binding affinity, bioactivity and selectivity of [β‐iPrPhe3]deltorphin I analogs: a (2S,3R) configuration of the iPrPhe3 residue in [β‐iPrPhe3]deltorphin I provided the most desirable biological properties with binding affinity (IC50 = 2 n m ), bioassay potency (IC50 = 1.23 n m in MVD assay) and exceptional selectivity for the δ‐opioid receptor over the µ‐opioid receptor (30 000). Further conformational studies based on two‐dimensional NMR and computer‐assisted molecular modeling suggested a model for the possible bioactive conformation in which the Tyr1 and (2S,3R)‐β‐iPrPhe3 residues adopt trans side‐chain conformations, and the linear peptide backbone favors a distorted β‐turn conformation. 相似文献
9.
JOËL BELLENEY BERNARD P. ROQUES MARIE-CLAUDE FOURNIE-ZALUSKI 《Chemical biology & drug design》1987,30(3):356-364
The preferential conformations of the δ selective opioid peptides DPLPE (Tyr-c[D-Pen-Gly-Phe-Pen]) and DTLET (Tyr-D-Thr-Gly-Phe-Leu-Thr) were studied by 400 MHz 1H n.m.r. spectroscopy in DMSO-d6 solution. In neutral conditions, the weak NH temperature coefficients of the C-terminal residue (Pen5 or Thr6), associated with interproton NH-NH and α-NH NOE's (ROESY experiments), indicated large analogies between the backbone folding tendency of both the linear and cyclic peptides. Various γ and/or β turns may account for these experimental data. A similar orientation of the N-terminal tyrosine related to the folded backbones is observed for the two agonists, with a probable γ turn around the amino acid in position 2. Finally, a short distance, about 10 Å, between Tyr and Phe side chains and identical structural roles for threonyl and penicillamino residues are proposed for both peptides. These results suggest the occurrence of similar conformers in solution for the constrained peptide DPLPE and the flexible hexapeptide DTLET. Therefore, it may be hypothesized that the enhanced δ selectivity of DPLPE is related to a very large conformational expense of energy needed to interact with the μ opioid receptor, a feature not encountered in the case of DTLET. These findings might allow peptides to be designed retaining a high affinity for δ opioid receptors associated with a very low cross-reactivity with μ binding sites. 相似文献
10.
Abstract: A protected tridehydropeptide containing (Z)‐β‐(3‐pyridyl)‐α,β‐dehydroalanine (ΔZ3Pal) residue, Boc‐Leu‐ΔZ3Pal‐Leu‐OMe ( 1 ), was synthesized via Erlenmeyer azlactone method. X‐ray crystallographic analysis revealed that the peptide 1 adopts an extended conformation, which is similar to that of a ΔZPhe analog, Boc‐Leu‐ΔZPhe‐Leu‐OMe ( 2 ). 相似文献
11.
Biological activity of synthetic β-endorphin (β-EP) analogs containing dermorphin or dynorphin-A-(1 – 13) structure has been investigated using the guinea pig ileum and the vas deferens of the mouse, rat and rabbit. Replacement of NH2-terminal 1–7 segment of camel β-EP [βc-EP-(1–7)] with dermorphin caused a great increase in opiate potency of the analog. [Dermorphin (1–7)] -βc-EP was 120 times more potent than βc-EP in the guinea pig ileum assay, 49 times more potent in the mouse vas deferens assay; and only 4 times more potent in the rat vas deferens assay. Replacement of NH2-terminal 1–13 segment of human β-EP [βh-EP-(1–13)] with dynorphin-A-(1–13) caused an increase in opiate potency in both the guinea pig ileum and rabbit vas deferens assays, a complete loss of potency in the rat vas deferens assay, and no change in the mouse vas deferens assay. In comparison with dynorphin-A-(1–13), the hybrid peptide was less potent in the guinea pig ileum assay as well as in mouse and rabbit vas deferens assay. It is suggested that βc-EP-(8–31) facilitates the dermorphin moiety to act on opiate μ and δ receptors but not on the ± receptor, while βh-(14–31) reduces the action of dynorphin on μ, δ and k receptors. 相似文献
12.
RONALD C. HAASETH TERESA ZALEWSKA PEG DAVIS HENRY I. YAMAMURA FRANK PORRECA VICTOR J. HRUBY 《Chemical biology & drug design》1997,50(3):171-177
Several para-substituted Phe4 analogues of the δ1-selective antagonist [l -Ala3]. DPDPE (DPADPE) were prepared and evaluated for their brain-binding and in vitro pharmacological effects. Unlike the p-haloPhe4 analogues of DPDPE and the deltorphins, similar analogues of DPADPE with electron-withdrawing groups substituted at the para-position of the Phe4 aromatic ring did not all have increased potency and selectivity for δ opioid receptors, but all retained high potency and selectivity for δ opioid receptors greater than DPDPE. © Munksgaard 1997. 相似文献
13.
WALTER F. SCHMIDT ROLLAND M. WATERS ALVA D. MITCHELL J.D. WARTHEN IRWIN L. HONIGBERG HERMAN VAN HALBEEK 《Chemical biology & drug design》1993,41(5):467-475
Synthesized β1- and β2-pentapeptide sequences corresponding to published adrenoceptor transmembrane activation site subtypes were investigated in vitro for selectivity in association for drug ligands of known selectivity. Both nuclear magnetic resonance spectroscopy and molecular mechanics demonstrated that structural differences among the corresponding pentapeptide activation-site sequences can explain agonist selectivity. Results suggest the agonists bind across the activation site loop on the second transmembrane α-helix by dipole/dipole interactions between a ligand and the peptide. Since electrostatic interactions within the membrane may determine the rate of intercellular ion flux, agonist association across the activation site sequence could thereby decrease electrostatic resistance to positive ion flux into the cell. Interactions between the peptides and the ligands may provide insight into the structures and mechanisms involved in association of ligands for the identical sequences on the β-adrenoreceptors. 相似文献
14.
BRIAN C. WILKES THI M.-D. NGUYEN GRAZYNA WELTROWSKA KATHARINE A. CARPENTER CAROLE LEMIEUX NGA N. CHUNG PETER W. SCHILLER 《Chemical biology & drug design》1998,51(5):386-394
Two different models for the receptor-bound conformation of δ-opioid peptide antagonists containing the N-terminal dipeptide segment H-Tyr-Tic (Tic = 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) have been proposed. Both models are based on spatial overlap of the Tyr and Tic2 aromatic rings and N-terminal amino group with the corresponding aromatic rings and nitrogen atom of the nonpeptide δ-antagonist naltrindole. However, in one model the peptide bond between the Tyr and Tic2 residues assumes the trans conformation, whereas in the other it is in the cis conformation. To distinguish between these two models, we prepared the two peptides H-Tyrψ[CH2NH]. Tic-Phe-Phe-OH and H-Tyrψ[CH2NH]. MeTic-Phe-Phe-OH (MeTic = 3-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) in which a cis peptide bond between the Tyr and Tic (or MeTic) residues is sterically forbidden. Both compounds turned out to be moderately potent δ-opioid antagonists in the mouse vas deferens assay. A molecular mechanics study performed with both peptides resulted in low-energy conformations in which the torsional angle (“ω1”) of the reduced peptide bond between Tyr and Tic (or MeTic) had a value of 180°(trans conformation) and which were in good agreement with the proposed model with all trans peptide bonds. Furthermore, this study confirmed that neither of these two peptides could assume low-energy conformations in which “ω1” had a value of 0°(cis conformation). Conformers with that same bond in the gauche- conformation (“ω1”= -60“) were also identified, but were higher in energy and showed no spatial overlap with naltrindole. On the basis of these results it is concluded that the receptor-bound conformation of δ-peptide antagonists containing an N-terminal H-Tyr-Tic-dipeptide segment must have all trans peptide bonds. © Munksgaard 1998. 相似文献
15.
Abraham Nudelman Yitschak Binnes Naomi Shmueli-Broide Yael Odessa J. Paul Hieble Anthony C. Sulpizio 《Archiv der Pharmazie》1996,329(3):125-132
Vinylogous (Groups III and V ) and acetylenologous (Group IV ) analogs of the classical β-adrenergic agents — stimulants and blockers — were prepared in order to evaluate the effect of degree of saturation, position of unsaturation and rigidity of the chain linking the aromatic ring and the amino containing functional group on biological activity. Derivatives from Group III , which represent 4-aryl-3-butenyl-2-ol-amine analogs of Group II , retained β1-adrenoceptor antagonist activity albeit substantially less potent (50–200-fold) than that possessed by their aryloxy counterparts. Consistent with the SAR for Group II compounds, substitution at position 2 of the aromatic ring yielded the most potent antagonists ( 5a, 5d, 5g ), with KB's ranging from 73–93 nM while 3,4-dichloro substitution ( 5e ) markedly reduced antagonist potency (KB = 2,400 nM). Agonist activity was also noted for 5b and 5d , suggesting that these compounds may be best classified as partial agonists. Representatives from Groups IV and V were inactive as antagonists at the β1-adrenoceptor confirming the importance of the spatial relationship between the hydroxyl and the amino nitrogen. 相似文献
16.
《Journal of labelled compounds & radiopharmaceuticals》2002,45(1):79-89
The enzyme, 15,15′‐β‐carotene dioxygenase (BCDOX), facilitates the oxidation of β‐carotene to yield retinal. This is a remarkable process in which one of 11 double bonds in β‐carotene is selectively oxidized. To further probe the mechanistic aspects of BCDOX, the synthesis of all‐trans‐[10′‐3H]‐8′‐apo‐β‐carotenoic acid is reported. This compound will be used as a photoaffinity labeling reagent to probe the β‐carotene binding pocket within BCDOX. The synthesis outlines a simple and efficient route for the incorporation of tritium at the 10′ olefinic carbon of 8′‐apo‐β‐carotenoic acid. Copyright © 2002 John Wiley & Sons, Ltd. 相似文献
17.
The use of peptides as drugs in pharmaceutical applications is hindered by their susceptibility to proteolysis and therefore low bioavailability. β‐Peptides that contain an additional methylene group in the backbone, are gaining recognition from a pharmaceutical stand point as they are considerably more resilient to proteolysis and metabolism. Recently, we reported two new classes of β ‐peptides, β 3‐ and β2‐peptides derived from l ‐aspartic acid and l ‐diaminopropionic acid, respectively. Here, we report the proteolytic stability of these β‐peptidic compounds and a mixed α /β‐peptide against three enzymes (pronase, trypsin and elastase), as well as, human serum. The stability of these peptides was compared to an α‐peptide. Peptides containing β‐linkages were resistant to all conditions. The mixed α /β‐peptide, however, exhibited proteolysis in the presence of trypsin and pronase but not elastase. The rate of degradation of the mixed α /β‐peptide was slower than that would be expected for an α‐peptide. In addition, these β‐peptides were not toxic to HeLa and COS‐1 cell lines as observed by MTT cytotoxicity assay. These results expand the scope of mixed α /β‐peptides containing β‐amino acids or small β‐peptide fragments as therapeutic peptides. 相似文献
18.
GRZEGORZ PIETRZYSKI BARBARA RZESZOTARSKA ZBIGNIEW KUBICA 《Chemical biology & drug design》1992,40(6):524-531
Solution conformations of three series of model peptides, homochiral Ac-Pro-L-Xaa-NHCH3 and heterochiral Ac-Pro-D-Xaa-NHcH3 (Xaa = Val, Phe, Leu, Abu. Ah) as well as αβ-unsaturated Ac-Pro-ΔXaa-NHCH3 [Δ Xaa =ΔVal, (Z)-ΔPhe, (Z)-ΔLeu, (Z)-ΔAbu] were investigated in CDCl3 and CH2Cl2 by 1H-, 13C-NMR, and FTIR spectroscopy. NH stretching absorption spectra, solvent shifts Δδ for NH (Xaa) and NHCH3 on going from CDCl3 to (CD3)2SO, diagnostic interresidue proton NOEs, and trans-cis isomer ratios were examined. These studies performed showed the essential difference in conformational propensities between homochiral peptides (L-Xaa) on the one hand and heterochiral (D-Xaa) and αβ-dehydropeptides (ΔXaa) on the other. Former compounds are conformationally flexible with an inverse γ-bend, a β-turn, and open forms in an equilibrium depending on the nature of the Xaa side chain. Conformational preferences of heterochiral and αβ-dehydropeptides are very similar, with the type-II β-turn as the dominating structure. There is no apparent correlation between conformational properties and the nature of the Xaa side chain within the two groups. The β-turn formation propensity seems to be somewhat greater in αβ-unsaturated than in heterochiral peptides, but an estimation of β-folded conformers is risky. 相似文献
19.
Ming‐De Wang Mozibur Rahman Inga‐Maj Johansson Torbjörn Bäckström 《Clinical and experimental pharmacology & physiology》2010,37(7):662-669
1. It is known that the α4‐subunit is likely to occur in the brain predominantly in α4β3δ receptors at extrasynaptic sites. Recent studies have revealed that the α1‐, α4‐, γ2‐ and δ‐subunits may colocalize extrasynaptically in dentate granule cells of the hippocampus. In the present study, we characterized a series of recombinant GABAA receptors containing human (H) and rat (R) α1/α4‐, β2/β3‐ and γ2S/δ‐subunits in Xenopus oocytes using the two‐electrode voltage‐clamp technique. 2. Both Hα1β3δ and Hα4β3γ2S receptors were sensitive to activation by GABA and pentobarbital. Contrary to earlier findings that the α4β3δ combination was more sensitive to agonist action than the α4β3γ2S receptor, we observed extremely small GABA‐ and pentobarbital‐activated currents at the wild‐type Hα4β3δ receptor. However, GABA and pentobarbital activated the wild‐type Rα4β3δ receptor with high potency (EC50 = 0.5 ± 0.7 and 294 ± 5 μmol/L, respectively). 3. Substituting the Hα4 subunit with Rα4 conferred a significant increase in activation on the GABA and pentobarbital site in terms of reduced EC50 and increased Imax. When the Hα4 subunit was combined with the Rβ3 and Rδ subunit in a heteropentameric form, the amplitude of GABA‐ and pentobarbital‐activated currents increased significantly compared with the wild‐type Hα4β3δ receptor. 4. Thus, the results indicate that the Rα4β3δ, Hα1β3δ and Hα4β3γ2S combinations may contribute to functions of extrasynaptic GABAA receptors. The presence of the Rα4 subunit at recombinant GABAA receptors containing the δ‐subunit is a strong determinant of agonist action. The recombinant Hα4β3δ receptor is a less sensitive subunit composition in terms of agonist activation. 相似文献
20.
Abstract: This review briefly surveys the conformational properties of guest ω‐amino acid residues when incorporated into host α‐peptide sequences. The results presented focus primarily on the use of β‐ and γ‐residues in αω sequences. The insertion of additional methylene groups into peptide backbones enhances the range of accessible conformations, introducing additional torsional variables. A nomenclature system, which permits ready comparisons between α‐peptides and hybrid sequences, is defined. Crystal structure determination of hybrid peptides, which adopt helical and β‐hairpin conformations permits the characterization of backbone conformational parameters for β‐ and γ‐residues inserted into regular α‐polypeptide structures. Substituted β‐ and γ‐residues are more limited in the range of accessible conformation than their unsubstituted counterparts. The achiral β,β‐disubstituted γ‐amino acid, gabapentin, is an example of a stereochemically constrained residue in which the torsion angles about the Cβ–Cγ (θ1) and Cα–Cβ (θ2) bonds are restricted to the gauche conformation. Hybrid sequences permit the design of novel hydrogen bonded rings in peptide structures. 相似文献