Biomedical subjects

J W Van Nispen

Publications and source records attributed to J W Van Nispen.

10 recordsLinked to original sources

PubMed1991

ACTH/MSH-like peptides inhibit the binding of dopaminergic ligands to the dopamine D2 receptor in vitro.

ACTH-(1-24) decreased the binding of the dopamine D2 receptor agonist, [3H]N-propylnorapomorphine ([3H]NPA), to rat striatal membranes in a concentration-dependent manner, with a Ki of 5 x 10(-7) M. Saturation curves for [3H]NPA binding in the presence of increasing concentrations of ACTH-(1-24) were performed. Scatchard analysis in the presence of ACTH-(1-24) revealed an increased dissociation constant (Kd), while the binding capacity (Bmax) was not affected by the peptide, suggesting an apparent competitive interaction between ACTH-(1-24) and [3H]NPA. ACTH-(1-24) also reduced the binding of the dopamine D2 receptor antagonist [3H]spiperone to striatal membranes, with a Ki of 10(-6) M. Much higher concentrations of ACTH-(1-24), up to 10(-4) M, were needed for the displacement of appropriate radiolabelled ligands from dopamine D1 receptors, serotonin 5-HT1A, serotonin 5-HT1B, muscarinic M1 acetylcholine and histamine H1 receptors. ACTH-(1-24) also inhibited the binding of [3H]spiperone to dopamine D2 receptors in membranes of the pituitary gland, the septum and the substantia nigra. ACTH-(1-39) and most ACTH fragments and analogs were less potent than ACTH-(1-24) in displacing [3H]NPA from the dopamine D2 receptor in striatal membranes. In general there was a relationship between displacing potency and chain length. ACTH-(7-16)-NH2 and benzyloxycarbonyl-ACTH-(8-16)-NH2, however, were more potent than ACTH-(1-24) in reducing the binding of [3H]NPA to dopamine D2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1990

Acid-catalyzed hydrolysis of peptide-amides in the solid state.

The hydrolysis of peptide-amides in the solid state at 4 degrees due to the presence of residual strong acid was investigated. It was found that even small molar excesses of these acids cause substantial deamidation in one day. The degree of amide hydrolysis depends not only upon the pKa and the volatility of the acid, but also upon the accessibility of the amide function; peptides with bulky C-terminal residues are more stable than the less-hindered ones.

Acids↗

PubMed1985

Inhibition of gamma-endorphin generating endopeptidase activity of rat brain by peptides: structure activity relationship.

gamma-Endorphin generating endopeptidase (gamma EGE) activity is an enzyme activity which converts beta-endorphin into gamma-endorphin and beta-endorphin-(18-31). The inhibitory potency on gamma EGE activity of neuropeptides and analogues or fragments of neuropeptides was tested. Dynorphin-(1-13) (IC50: 0.14 microM), human beta-endorphin-(1-31) (IC50: 15.5 microM), porcine ACTH-(1-39) (IC50: 6.3 microM), and substance P (IC50: 26 microM) had an inhibitory activity on gamma EGE activity. beta-Endorphin-(18-31) (IC50: 0.35 microM) but not gamma-endorphin potently inhibited gamma EGE activity. The IC50 of poly (Lys)40-60 was 0.8 microM. It is concluded that 1) gamma EGE activity is strongly inhibited by its product beta-endorphin-(18-31), 2) the enzyme is strongly inhibited by peptides with an aromatic amino acid at the NH2-terminal and/or basic amino acids in the COOH-terminal of the peptide chain.

Amino Acid Sequence↗

PubMed1983

Oxytocin is a precursor of potent behaviourally active neuropeptides.

An oxytocin fragment which accumulated during the incubation of oxytocin with brain synaptic membranes was chemically characterized as the hexapeptide pGlu-Asn-Cys(Cys)-Pro-Leu-Gly-NH2 [( pGlu4, Cyt6]OXT-(4-9]. This peptide was approximately a hundred times more potent than oxytocin in attenuating memory consolidation as tested in a passive avoidance test situation; the dose-response relationship was bell-shaped. The des-glycinamide derivative [pGlu4, Cyt6]OXT-(4-8) was nearly as active, but showed a linear dose-response relationship. The data indicate that oxytoxin can act as precursor for potent behaviourally active neuropeptides.

Animals↗

PubMed1979

Cyclized dipeptide model for a beta-bend.

A cyclic dipeptide in which L-Ala-Gly was cyclized with epsilon-aminocaproic acid has been synthesized as a model for a beta-bend. Its conformational properties have been examined by means of conformational energy calculations and nuclear magnetic resonance, infrared, Raman, and circular dichroism spectroscopy in various solvents. These calculations and experiments suggest that a type II beta-bend exists in the Ala-Glymoiety, with an NH...O = C hydrogen bond in the epsilon-aminocaproic acid portion of the molecule, and that the molecule adopts a unique conformation in solution. In contrast, an open-chain analog of this compound exists in solution as an ensemble of conformations but with a significant amount of a type II beta-bend structure in the ensemble.

Circular Dichroism↗

PubMed1977

Synthesis and biological activities of two ACTH-analogues containing L-norarginine in position 8.

Two new ACTH-analogues, an octadecapeptide amide and a tetracosapeptide containing the lower homologue of arginine (norarginine) in position 8, have been synthesized by the generally accepted method. Special attention was paid to the synthesis of the required tetrapeptide representing the 7-10 sequence, which was obtained either by direct introduction of L-nitronorarginine or by amidination of the gamma-amino function in a protected peptide containing alpha, gamma-diaminobutyric acid. Biological activity determination showed that the shortening e arginine side chain in position 8 results in the formation of active ACTH-analogues.

Adrenocorticotropic Hormone↗

PubMed1977

Des-Nalpha-acetyl-alpha-melanotropin: a synthetic substrate for specific N-terminal directed enzymatic acetylation.

Application of the 2-methylsulfonylethyloxycarbonyl group for temporary amino protection enables the synthesis from one precursor of des-Nalpha1-acetyl-alpha-MSH, the two mono N-acetylated forms (in positions I and II) and the diacetyl form of this tridecapeptide amideq The free tridecapeptide amide, although structurally unrelated to the normal substrate, was recognized by an enzyme occurring in calf eye-lens tissue. The product of the enzymatic reaction was exclusively alpha-MSH. Partial sequences derived from the N-terminus were less rapidly acetylated or not at all, depending on their chain length. The enzyme, therefore, appears to direct its activity to free N-terminal alpha-amino groups of peptides exceeding a certain critical chain length. Acetylation of epsilon-amino functions did not occur.

Acetylation↗

PubMed1977

Investigation of the role of tryptophan in alpha-MSH. Replacement by L-pentamethylphenylalanine and L-phenylalanine.

Two analogues of alpha-MSH are described, in which the tryptophan residue occuring in position 9 of the natural hormone has been replaced by pentamethylphenylalanine and phenylalanine, respectively. The analogues were synthesized via a conventional procedure and the [Phe9]-analogue also by a semi-synthetic approach, which demonstrated the favourable properties of the applied, new amino-protecting Msc function for this purpose. The widely different electron donor properties of the substituted residues were accompanied by a large difference in melanocyte stimulating activity of the analogues. The [Pmp9]-analogue, having donor properties comparable to those of the natural compound, was four to five times more active than the analogue containing the poorly donating Phe residue. The opposite effect was noted in in vivo lipolysis in rabbits.

Amino Acid Sequence↗

PubMed1975

Synthesis and charge-transfer properties of two acth analogues containing pentamethylphenylalanine in position 9.

In order to investigate the possible role of the Trp residue in ACTH as a change-transfer donor in the activation of ACTH receptors, two ACTH analogues (beta-corticotrophins (I-24) with L-Ser1 and D-Ser1, respectively) containing pentamethylphenylalanine instead of Trp have been synthesized. In these syntheses a new, alkaline-labile, amino-protecting group, the methylsulphonylethyloxycarbonyl group, was employed. The association constants of ACTH (I-24) and (Pmp9)-ACTH (I-24) with the water-soluble acceptor paraquat, were nearly equal.

Acetylation↗

PubMedDate not supplied

Des-enkephalin-gamma-endorphin (DE gamma E): biotransformation in rat, dog and human plasma.

Biotransformation of [3H-Lys9] DE gamma E was investigated after in vitro incubation of the tritiated peptide with rat, dog and human plasma. In addition, its metabolite profile in blood was studied following intravenous administration to rats and dogs. Half-lives for the in vitro disappearance of DE gamma E in plasma were 13.0 +/- 0.8 min (dog), 15.7 +/- 1.2 min (rat) and 19.2 +/- 0.9 min (human), indicating very rapid degradation of the peptide by proteolytic enzymes. Biotransformation products were identified on the basis of co-chromatography on HPLC with synthetic reference peptides. The six principal fragments appeared to be beta-endorphin (beta E) sequences 7-17, 8-17, 9-17, 6-15, 7-15 and 8-15. The abundance of beta E6-15, beta E7-15 and beta E8-15 in rat and human plasma suggests preferential, subsequent carboxypeptidase and aminopeptidase mechanisms, whereas in dog plasma DE gamma E is predominantly degraded by aminopeptidase activities (major peptide metabolites: beta E7-17 and beta E8-17). In the in vivo studies with rats and dogs the same radioactive peptide fragments were detected in blood as found in the in vitro experiments with plasma. In both species their blood levels were already maximal within a minute after intravenous administration of the parent peptide, thereafter they declined rapidly. 3H-Lysine was the main radioactive metabolite in vivo, exceeding 70% of total radioactivity in rat and dog blood 10 min after 3H-DE gamma E dosing.

Animals↗