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M Marastoni

Publications and source records attributed to M Marastoni.

70 records · Page 4Linked to original sources
PubMed1986

Synthesis and opioid activity of dermorphin tetrapeptides bearing D-methionine S-oxide at position 2.

Eight new dermorphin tetrapeptides, X-Tyr-D-MetO-Phe-aa-Y (X = H, H2N = C(NH); aa = Gly, 2-aminoethanol, sarcosine; Y = NH2, NH-alkyl), were prepared and tested for opioid activity. They show dose-related naloxone-reversible opioid effects in vitro and in vivo. H-Tyr-D-MetO-Phe-Gly-NH2 (I) (guinea pig ileum IC50 = 13.6 nM; tail-flick ED50 = 1.97 pmol/mouse, icv, and 0.65 mumol/kg, sc), though less effective in the periphery, has central activities higher than those of dermorphin H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2. Following intracerebroventricular or subcutaneous administrations in mice, I is about respectively 1500 and 17 times as potent an analgesic as morphine.

Analgesics, Opioid↗
PubMed1986

Synthesis and biological activity of carboxyl terminally extended dermorphins.

Dermorphinoyl(DMR)-glycine, DMR-sarcosine and DMR-glycyl-arginine have been prepared in order to examine the effect of C-terminal extension of dermorphin (H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2) on opioid activity. On GPI preparation the addition of Gly, Sar, or Gly-Arg to the carboxyl terminus of dermorphinoic acid was detrimental to mu activity: dermorphinoyl-derivatives, in fact, retain only 5-20% of dermorphin potency. Following intracerebroventricular administration (tail-flick test), whereas the analgesic activities of compounds showed the trend dermorphin greater than DMR-Sar greater than DMR-Gly-Arg greater than DMR-Gly greater than morphine, the nonapeptide displayed highest activity after subcutaneous injection in mice: DMR-Gly-Arg was 2.5 and 10 times more potent than dermorphin and morphine, respectively.

Amino Acid Sequence↗
PubMed1986

Dehydro-dermorphins. I. Influence of the stereo-orientation of aromatic groups in dermorphin-(1-5)-peptides to opioid activity.

Dehydrophenylalanine having the Z-configuration (delta Phe) and D-Phe were incorporated in positions 3 and/or 5 into dermorphin-(1-5)-peptide amide (H-Tyr-D-Ala-Phe-Gly-Tyr-NH2) in order to study the effect of structure or configurational changes. On GPI preparation, whereas the activity of [L-Phe5]-pentapeptide was fourfold higher than parent peptide and comparable to that of dermorphin, the substitution of Phe3 by its D-enantiomer was barely tolerated. The pentapeptides containing delta Phe in positions 3 and/or 5 displayed even lower potency: particularly the unsaturation at position 3 alone or at position 3 and 5 was very detrimental to mu activity.

Animals↗
PubMed1986

Dehydro-dermorphins. II. Synthesis and biological activity of unsaturated dermorphin hexa and heptapeptides.

The Phe3 and/or Tyr5 residues in dermorphin (H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2) and its N-terminal hexapeptide-amide were replaced by delta-Phe or by Phe5 in order to examine the effect on opioid activity. On GPI preparation, the substitution of Phe5 for Tyr5 was well tolerated, whereas the hexa and heptapeptides containing delta Phe in position 3 and/or 5 displayed low potency. The unsaturation at position 3 alone or at positions 3 and 5 was particularly detrimental to mu activity. In the tail flick test, the influence of unsaturation or substitution at positions 3 and 5 generally matched the results of the in vitro assay. Dehydropeptides showed comparatively low antinociceptive effects and [Phe5] analogues displayed about 50% of the analgesic potency of the original peptides.

Animals↗
PubMed1985

Opioid peptides. VIII. Synthesis and preliminary biological activity of [D-Phe3]- or [alpha,beta-dehydro-Phe3]dermorphin tetrapeptides.

We describe the synthesis and preliminary in vitro pharmacological testing of two new tetrapeptide analogues of the opioid heptapeptide dermorphin H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2. The replacement of Phe3 by its D-enantiomer was hardly if at all tolerated. The unsaturated analogue carrying the phenyl ring of the delta Phe3 residue in the Z-configuration, was almost inactive.

Animals↗
PubMed1985

Synthetic tetrapeptides related to dermorphin: potent long lasting analgesic action following subcutaneous administration.

To examine the opioid properties of D-MetO2-dermorphin tetrapeptides, eight new analogues based on the following formula, X-Tyr-D-MetO-Phe-aa-Y, were prepared. All these peptides show dose-related naloxone-reversible opioid effects in vitro and in vivo. Substitution of Sar or Gly-ol for Gly4 were well tolerated by the isolated guinea pig-ileum preparation as well as in the tail-flick test, while alkyl-amidation of the C-terminal proved detrimental. The central activity of H-Tyr-D-MetO-Phe-Gly-NH2, the most potent compound in the series, was higher than that of dermorphin. Following intracerebroventricular or subcutaneous administrations in mice, H-Tyr-D-MetO-Phe-Gly-NH2 was about 1500 and 17 times as analgesic as morphine, respectively.

Amino Acid Sequence↗
PubMed1985

Synthesis and pharmacological activity of partially modified retro-inverso dermorphin tetrapeptides.

We studied the effect of partial retro-inverso modification of selected peptide bonds of N-terminal tetrapeptide analogues of dermorphin (H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2). Among the 14 compounds synthesized and tested for opioid activity, some tetrapeptides have the C-terminus carrying different amide moieties; retromodifications concern the Phe-Gly bond (Ia-f) and/or the C-terminal carboxamide function (IIIa-d, IIa-d). All pseudotetrapeptide derivatives showed opioid activity in vitro and in vivo. The most potent compounds (II) have a biological potency comparable with that of the original tetrapeptides in the guinea pig ileum preparation and in the mouse tail-flick test after intracerebral or subcutaneous administration.

Animals↗
PubMed1985

Synthesis and opioid activity of partial retro-inverso analogs of dermorphin.

We studied the effect of partial retro-inverso modification of selected peptide bonds of dermorphin (H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2. The modifications concern two consecutive peptide bonds (Phe3-Cly4-Tyr5, I) or a single one (Gly4-Tyr5-, II or Phe3-Gly4, III). All pseudoheptapeptides showed low opioid activity in the in vitro and in vivo tests. Compound III has a biological potency comparable to that of morphine but only 2-5% of original dermorphin when tested in guinea pig ileum preparation and in mice tail-flick assay after intracerebro or subcutaneous administration.

Analgesia↗
PubMed1984

Synthesis and opioid activity of [Sar4]dermorphin-tetrapeptide analogues.

The modification of the dermorphin-(1-4)-tetrapeptide structure led to analogues with potent opioid activity in vitro and in vivo. [Sar4]Tetrapeptides such as H2N-CH(NH)-Tyr-D-Ala-Phe-Sar-D-NH-CH(CH3)C6H5 (VII) whose terminal amino group is replaced by the guanidino function and whose C-terminus is amidated by (R)-(+)-alpha-methylbenzylamine, show peripheral and central opioid activities comparable to or higher than those of dermorphin. The potency of VII in the different tests was as follows: guinea-pig ileum (GPI) IC50 = 0.09nM, mouse Vas deferens (MVD) IC50 = 0.69nM, tail-flick ED50 = 8.91 pmol/mouse, i.c.v. and 4.54 mumol/kg, s.c. This dermorphin-(1-4)-tetrapeptide derivative is about 650 and 950 times as active as morphine in the two in vitro tests, respectively. The MVD/GPI potency ratio of the new peptides suggests a mu-type agonist behaviour.

Animals↗
PubMed1982

Opioid peptides. Structure-activity relationships in dermorphin tetrapeptides. I.

Characterisation and pharmacological data of twelve synthetic tetrapeptide analogs of dermorphin (opioid heptapeptide) are reported. An N-terminal tetrapeptide free acid or ester is less potent that the corresponding amide. Whereas substitution of Gly4 by another aminoacid residue is well tolerated, substitution of D-Ala2 by D- or L-alpha-aminoxypropionic acid causes a complete loss of activity. Finally, guanidination of the tetrapeptides results in an increase of peripheral and central opioid activity.

Animals↗
PubMedDate not supplied

Reversed-phase HPLC study on the in vitro enzymic degradation of dermorphin.

A high-performance liquid chromatographic (HPLC) method for the separation of the opioid heptapeptide dermorphin and related fragments has been developed. The chromatographic system was applied in the study of the kinetics of degradation of dermorphin (Der) in various tissues. Der was found to be extremely resistant to human and rat plasma (T 1/2 greater than 180 min). Upon incubation with homogenates of rat brains and kidneys, Der was cleaved with a half-life of 20.8 +/- 2.2 min and 2.4 +/- 0.3 min respectively. The catabolite formed was identified, in both tissues, as the N-terminal tetrapeptide H-Tyr-D-Ala-Phe-Gly-OH. The stability to rat kidney and brain of the N-terminal hexa- and pentapeptides and of the [4 psi 5, NHCO] Der analogue was also investigated. The nature of the enzyme systems involved in the in vitro degradations is discussed.

Analgesics, Opioid↗
PubMedDate not supplied

Symmetry-based inhibitors of HIV-1 protease. Design, synthesis and preliminary structure-activity studies of acylated 2,3-diamino-1-hydroxypropanes and 2,4 diamino-1-hydroxybutanes.

Two series of peptidomimetics containing a novel C(2) pseudosymmetrical hydroxyalkyldiamino core structure were prepared from amino acid starting materials and tested for inhibitory activity against the HIV-1 protease (HIV-1 Pr) and the virus in cell culture. In the 2,3-diamino-1-hydroxypropane series, compound 6a, containing P1/P1(I) benzyl and P2/P2(I) Fmoc substituents, displayed modest HIV-1 Pr inhibition (IC(50) = 430 nM). The corresponding 2,4-diamino-1-hydroxybutane derivative (6b) was the best inhibitor of the series (IC(50) = 160 nM). Interestingly, 6a and 6b showed satisfactory inhibition of HIV replication in cell culture (ED(50) = 340 and 110 nM, respectively), a result which suggests good cell membrane penetration by this class of compounds.

Acylation↗