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Biomedical subjects

C H Stammer

Publications and source records attributed to C H Stammer.

At least 19 recordsLinked to original sources
PubMed1992

Inhibition of pig kidney L-aromatic amino acid decarboxylase by 2,3-methano-m-tyrosines.

Both racemic (E)- and (Z)-2,3-methano-m-tyrosines (9E and 9Z) have been synthesized from a common intermediate, monoester (Z)-1-(ethoxycarbonyl)-2-[3-[(2-methoxyethoxy)methoxy]phenyl] cyclopropanecarboxylic acid (5). Quinine and ephedrine, respectively, were used to resolve their N-tert-butoxycarbonyl (Boc) derivatives. Among the compounds prepared, the (+)-(E)-diastereomer of 9 is the most potent inhibitor of L-aromatic amino acid decarboxylase (Dopa decarboxylase), having a Ki of 22 microM, with the (-)-Z-diastereomer (9Z) second at Ki = 49 microM. (+)-9E is a 45-fold more potent inhibitor of DDC than its acyclic analogue, D-m-tyrosine.

Animals↗
PubMed1990

Synthesis and conformational studies by 1H- and 13C-NMR spectroscopy of a novel, sterically constrained analogue of thyrotropin-releasing hormone.

A novel thyrotropin-releasing hormone (TRH) analogue, [2,4-MePro3]-TRH (2,4-MePro: 2-carboxy-2,4-methanopyrrolidine), has been synthesized using a rapid solid phase peptide synthesis method, and its conformational properties investigated by one- and two-dimensional (2D) nmr spectroscopy and by proton Overhauser measurements. Following a published approach, calibrated interproton Overhauser effects were used together with distance geometry analysis to deduce that the single conformation of the His-2,4-MePro tertiary amide bond is trans in aqueous solution. This conclusion was corroborated by 2D dipolar-correlated (NOESY) spectroscopy. A preferentially extended conformation is indicated by the nmr data, similar to that of TRH. The phi, psi conformational space of 2,4-MePro is, however, significantly different from that of trans proline and the structural consequences of these differences at the C-terminus are discussed. The distribution of histidine side-chain conformations in the TRH analogue was deduced from coupling constants and from the short-range interaction between the imidazole ring and one of the prochiral faces of the 2,4-MePro side chain.

Carbon Isotopes↗
PubMed1989

Enzyme inhibition by dipeptides containing 2,3-methanophenylalanine, a sterically constrained amino acid.

Both isomers of (E)-2,3-methanophenylalanine (delta EPhe), a sterically restricted amino acid, were incorporated into peptides in order to examine their possible enzyme inhibitory activity. Both (2R,3S)- and (2S,3R)- delta EPhe-Phe(or Leu)-OMe were found to inhibit effectively the hydrolysis of Ac-Tyr-OEt by chymotrypsin in a competitive manner. The ester groups of these dipeptides were quite resistant to chymotrypsin hydrolysis, and the delta EPhe-Phe peptide bond was also entirely stable. The inhibition constant (Ki) of the most potent dipeptide of H-(2R,3S)-delta EPhe-Phe-OMe was 0.16 mM at 25 degrees C. The inhibitory action of delta Phe-containing peptides was found to depend on the configuration of the delta Phe residue. The electrophilic nature of the cyclopropane ring which is conjugated with both the phenyl ring and the ester carbonyl group appears to be relevant to the inhibitory activity. Fully irreversible inactivation of chymotrypsin was achieved by its incubation with H-(2R,3S)- delta EPhe-Leu-OMe. An enzyme carboxylate group is thought to be responsible for nucleophilic attack on the cyclopropane ring leading to irreversible inactivation.

Chemical Phenomena↗
PubMed1989

Conformational properties of 2,3-methanopyroglutamic acid in peptides: NMR and x-ray diffraction studies.

The effects of replacing L-pyroglutamic acid with the cyclopropane analogue 2,3-methanopyroglutamic acid (2,3-MeGlp) on conformation and enzymatic stability have been investigated in 2,3-MeGlp-NHMe and the novel thyrotropin releasing hormone (TRH) analogue [2,3-MeGlp1]-TRH by x-ray diffraction and nmr. While 2,3-MeGlp-NHMe adopts a folded conformation (small psi angle) in the solid state, several conformations are available to the molecule in solution. 1H-nmr of the diastereomeric mixture [(+/- )-2,3-MeGlp1]-TRH indicates a close orientation of the pyrrolidone and imidazole rings. The 2,3-MeGlp-His amide bond is considerably more stable to pyroglutamate aminopeptidase than the Glp-His bond in TRH.

Magnetic Resonance Spectroscopy↗
PubMed1989

Crystallographic characterization of conformation of 1-aminocyclopropane-1-carboxylic acid residue (Ac3c) in simple derivatives and peptides.

The molecular and crystal structures of the C alpha,alpha-dialkylated alpha-amino acid residue 1-aminocyclopropane-1-carboxylic acid hemihydrate (H2+-Ac3c-O-.1/2 H2O) and nine derivatives and dipeptides have been determined by X-ray diffraction. The derivatives are pBrBz-Ac3c-OH, Piv-Ac3c-OH, Z-Ac3c-OH, the alpha-and beta-forms of t-Boc-Ac3c-OH, Z-Ac3c-OMe, and the 5(4H)-oxazolone from pBrBz-Ac3c-OH; the dipeptides are H-(Ac3c)-OMe and c(Ac3c)2. The values determined for the torsion angles about the N-C alpha (phi) and C alpha-C' (psi) bonds for the single Ac3c residue of Piv-Ac3c-OH, the alpha- and beta-forms of t-Boc-Ac3-OH and Z-Ac3c-OMe, and the C-terminal Ac3c residue of H-(Ac3c)2-OMe correspond to folded conformations in the "bridge" region of the Ramachandran map. The structures of pBrBz-Ac3c-OH and Z-Ac3c-OH, however, are unusual in having a semi-extended conformation for the phi, psi angles. The N-terminal Ac3c residue of H-(Ac3c)2-OMe adopts a novel type of C5 conformation, characterized inter alia by an (amino) N. . .H-N (peptide) intramolecular hydrogen bond. While the acyl N alpha-blocking groups form trans amides (pBrBz-Ac3c-OH and Piv-Ac3c-OH), the urethane groups may adopt either the trans [Z-Ac3c-OH and t-Boc-Ac3c-OH (alpha-form)] or the cis amide conformations [t-Boc-Ac3c-OH(beta-form) and Z-Ac3c-OMe]. The five- and six-membered rings of the 5(4H)-oxazolone and the 2,5-dioxopiperazine, respectively, are planar. The four independent molecules in the asymmetric unit of the free alpha-amino acid are zwitterionic.

Amino Acids↗
PubMed1988

A highly selective ligand for brain delta opiate receptors, a cyclopropyl(E)Phe(4)-enkephalin analog, suppresses mu receptor-mediated thermal analgesia by morphine.

[D-Ala(2)(2R,3S)-delta(E)Phe(4)Leu(5)]enkephalin (CP-OH) [delta denoting cyclopropyl; superscript E indicating the E-configuration about the cyclopropane ring], a highly selective opioid ligand for delta receptors in rat brain, but not for those in the mouse vas deferens, was examined for in vivo biological activities by intracerebroventricular administration. CP-OH (5-20 micrograms) showed no analgesic activity in the hot plate (51 degrees C) test using rats. However, it suppressed completely the analgesic effects of intraperitoneally administered morphine (3 mg/kg rat) in a dose-dependent manner. CP-OH showed no binding affinity for brain kappa receptors to which dynorphin, an opioid peptide that inhibits morphine analgesia, binds predominantly. These results suggest that, besides the conventional delta receptors which mediate analgesia, the rat brain contains another delta-like receptor which has a modulatory role to attenuate morphine-induced analgesia mediated through the mu receptors, and that this modulatory receptor does not exist in the mouse vas deferens.

Analgesia↗
PubMed1987

delta EPhe4-enkephalin analogs. Delta receptors in rat brain are different from those in mouse vas deferens.

Conformationally restricted enkephalin analogs containing E-cyclopropylphenylalanine (delta EPhe), [D-Ala2, (2R,3S)-delta EPhe4,Leu5]enkephalin and its (2S,3R) isomer, were evaluated in receptor-binding assays using rat brain and in assays using muscle preparations. The (2S,3R) isomer was almost completely inactive in all assays. In contrast, the (2R,3S) isomer showed a very high affinity for the delta and a very weak affinity for the mu receptors in rat brain. The extent of delta affinity and the selectivity of this isomer were almost equal to those of [D-Pen2,D-Pen5]enkephalin. However, the (2R,3S) isomer was inactive in both the mouse vas deferens and guinea pig ileum assays, and showed no antagonistic activity in these tissues. These results indicate that the (2R,3S) isomer interacts with the delta receptors in rat brain, but not with those in the mouse vas deferens, and they suggest that the delta receptors in the central and peripheral nervous systems are different from each other.

Animals↗
PubMed1987

Cyclopropane amino acid ester dipeptide sweeteners.

A series of esters of L-aspartyl-1-aminocyclopropane carboxylic acid has been prepared and their sweet tastes determined. The sweetest ester prepared was about 300 times sweeter than sucrose. An attempt to use basic conditions during preparation of the dipeptide allyl ester led to succinimide formation of the aspartyl peptide even though the beta-carboxyl group was protected by a t-butyl ester function. The X-ray structure of the propyl ester (1c) was determined and its conformation is discussed.

Aspartame↗
PubMed1986

Synthesis and receptor binding affinity of both E- and Z-dehydrophenylalanine4 enkephalins.

The dehydrophenylalanine4-enkephalin having the E-configuration (delta EPhe; phenyl and C = 0, cis) was prepared by photoisomerization of the Z-isomer with 3100 A light, followed by reversed-phase HPLC separation of the resulting mixture of the Z- and E-isomers. In the radioligand receptor binding assays, the E-isomer of [D-Ala2, delta Phe4, Leu5]enkephalin exhibited an extremely diminished affinity as compared with the Z-isomer, namely 150-260-fold loss of affinity for the delta and mu opiate receptors. The results indicate that the interrelationship of the Tyr1 and Phe4 residues in the enkephalin molecule seems to be of great importance in receptor recognition.

Animals↗
PubMed1985

Conformational preferences of cyclopropyl peptides. Crystal structure of (E)-DL-1-benzamido-1-methoxycarbonyl-2-chlorcyclopropane (BCP).

Crystal structure analysis of (E)-DL-1-benzamido-1-methoxycarbonyl-2-chlorocyclopropane (C12H12NO3Cl) is reported. The phi' (about N1-C1 bond) and psi' (about C1-C11 bond) torsional angles for this compound are -62.5 degrees and -33.0 degrees, respectively, and are close to the phi, psi values of the 3(10) helix and the alpha-helix. Semi-empirical potential energy calculations are performed on a cyclopropyl dipeptide which is a special case of alpha,alpha-disubstituted dipeptide where the alpha-carbon and the two substituent carbon atoms form a 3-membered ring. Our calculations show that different types of helics: alpha-, gamma-, pi-, omega-, 3(10-) and delta-helices, are energetically favorable. Another interesting possibility is the formation of a cyclic pentapeptide with five-fold symmetry. The effect of substitutions on C beta atom are also studied with the help of potential energy maps. Selective substitutions on C beta atom may be used effectively to restrict either phi or psi values into a very narrow range.

Cyclopropanes↗
PubMed1984

Importance of the stereo-orientation of aromatic groups in enkephalins to opiate receptor recognition.

PO +Dehydrophenylalanine (delta Phe) having the E-configuration (delta EPhe ; phenyl and C = O cis) was incorporated into [Leu5]-enkephalin in order to restrict its conformation. Compared with the Z-isomer, in the radio-ligand receptor binding assays, [D-Ala2, delta EPhe4 , Leu5] enkephalin showed drastically decreased potency for the delta and mu opiate receptors, i.e., 260- and 150-fold loss of affinity, respectively. The results strongly indicate that the opiate receptors require the Z-configuration (phenyl and C = O, trans) of the delta Phe4 residue and may require a specific interrelationship between the aromatic rings of the Tyr1 and Phe4 residues in the molecule for binding. The conformation of [Leu5]-enkephalin specific for the delta receptors was analyzed and a comparison made with its crystal structure recently elucidated.

Animals↗
PubMed1983

Synthesis and biological activity of delta Phe4-enkephalins.

The delta Phe4-enkephalins have been synthesized and examined in an in vitro receptor binding assay and an in vivo tail flick analgesia test. The delta Phe4 residue was derived from Boc-Gly-Phe(beta-OH)-OH by spontaneous dehydration and azlactonization. The dipeptide azlactone was coupled directly with H-Leu-OBzl to yield a tripeptide which was converted into the pentapeptides after stepwise coupling with two amino acids using the water soluble EDC-HOBt method. Dehydroenkephalins were liberated with hydrogen fluoride in the presence of anisole. In the radioligand binding assay which did not contain an enzyme inhibitor [D-Ala2, delta Phe4, Leu5] enkephalin was almost twice as active as saturated [D-Ala2, D-Leu5]-enkephalin. The delta Phe4-enkephalins exhibited a considerably diminished activity as compared with the saturated peptide in the in vivo analgesic assay. These results are discussed with regard to the enzyme stability and receptor preference of dehydroenkephalins.

Analgesia↗