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Biomedical subjects

R Tomatis

Publications and source records attributed to R Tomatis.

At least 91 records · Page 5Linked to original sources
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

Prolactin releasing and luteinizing hormone inhibiting activity of dermorphin shorter homologues in the rat.

Dermorphin, a heptapeptide isolated from the skin of the frogs Phillomedusa sauvagei and Phillomedusa rhodei, is endowed with potent peripheral and central opioid-like activity. Intracerebroventricular (icv) injection of dermorphin (31.2, 62.5 and 125 pmol/100g) induced in ovariectomized (OVX) rats dose related rises and decreases in prolactin (PRL) and luteinizing hormone (LH) levels, respectively. The aim of this work was to evaluate the same endocrine responses after administration of shorter peptide amide homologues, related to the N-terminal sequence of dermorphin. These compounds retain a substantial analgesic activity although the latter decreases with the decrease in the number of amino acid residues. Icv administration of the hexapeptide homologue (dermorphin 1-6 amide) to OVX rats did not induce any PRL rise or LH inhibition, even at the high dose of 250 pmol/100g. The pentapeptide (dermorphin 1-5 amide), instead, increased PRL and decreased LH secretion, although the effect was significant only at the dose of 250 pmol/100g. Administration of the tetrapeptide (dermorphin 1-4 amide) induced a significant PRL rise and LH inhibition at both the doses of 125 and 250 pmol/100g. The tetrapeptide was the smallest fragment of the dermorphin moiety which caused endocrine responses while the tripeptide (dermorphin 1-3 amide) was completely ineffective in this context. These data indicate that a complete dissociation exists between the behavioral and endocrine effects of the dermorphin homologues examined. In fact, shorter dermorphins whose analgesic potency was directly related to the number of amino acids, exhibited an opposite pattern in evoking endocrine effects.

Analgesics↗
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

Prolactin and growth hormone responses to dermorphin in patients with prolactin-secreting pituitary adenoma.

We have recently shown that dermorphin (D), a new potent opioid peptide (H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2) stimulates prolactin (PRL) and growth hormone (GH) secretion in humans. In 11 patients with a PRL-secreting pituitary adenoma (eight microprolactinomas and three macroprolactinomas with suprasellar extension), diagnosed by pituitary dynamic function tests, and radiological evidence with confirmation at surgery, the PRL and GH responses to D were studied to evaluate the effect of pathological hyperprolactinemia on the opioid-induced secretion of GH and PRL. No PRL response to D was observed in all 11 patients. Plasma GH increased after D in all patients, except in three patients bearing a macroprolactinoma. This study shows that the effect of D on PRL and GH secretion can be dissociated in patients with PRL-secreting pituitary adenoma, perhaps for a different derangement in the hypothalamic-pituitary mechanism(s) underlying the opioidergic regulation of GH and PRL secretion. In addition our data indicate that D can be employed as a useful opioid probe in humans.

Adenoma↗
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

The effects of dermorphin on the endocrine system in man.

This paper summarizes the results of our recent studies in a group of healthy subjects on the endocrine effects of the new potent opioid peptide, dermorphin (H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2), originally isolated from amphibian skin. Intravenous infusion (5.5 microgram/kg/min for 30 min) of dermorphin (D) significantly increased plasma levels of prolactin (PRL), growth hormone (GH), thyrotropin (TSH) and renin activity (PRA), but decreased plasma levels of cortisol. D produced a small decrease in ACTH, and a small increase in plasma aldosterone. Pretreatment with the opioid receptor antagonist naloxone (N) suppressed the PRL and TSH response to D, blunted the D-induced GH and PRA increase, and completely prevented the D-induced plasma cortisol decrease, but enhanced plasma cortisol and ACTH levels. These data indicate that the action of D is mediated through opioid receptors, and are consistent with the conclusion that: (1) D, a new opioid peptide, can stimulate PRL, GH and TSH release in humans; (2) D increases PRA levels, perhaps via activation of the sympathetic nervous system, providing evidence that opioid peptides may exert an influence on renin secretion; (3) D suppresses plasma cortisol levels, by affecting ACTH secretion, corroborating previous observations that opioid peptides might affect the function of the pituitary-adrenocortical axis.

Adrenocorticotropic Hormone↗
PubMed1985

A conformational study of the opioid peptide dermorphin by one-dimensional and two-dimensional nuclear magnetic resonance spectroscopy.

Dermorphin, a natural peptide opioid containing a D-Ala2 residue, has been studied in dimethyl sulfoxide (DMSO) solution by means of several one-dimensional and two-dimensional 1H nuclear magnetic resonance (NMR) methods at various fields from 80 to 600 MHz. The combined use of conventional NMR parameters and of nuclear Overhauser effect effects points to an essentially extended structure. This conformation may be, in part, the result of strong interaction of the amide groups with DMSO molecules.

Dimethyl Sulfoxide↗
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↗
PubMed1985

Dermorphin reduces the metyrapone-evoked release of adrenocorticotropin, beta-endorphin, and beta-lipotropin in man.

The aim of this study was to investigate further the influence of dermorphin (D), a new potent opioid peptide (H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2), on the functional activity of the pituitary-adrenocortical system in man. Six normal men were treated with oral metyrapone to stimulate the secretion of ACTH, beta-lipotropin, and beta-endorphin. In these subjects, significant suppression of metyrapone-evoked release of ACTH and related peptides occurred during D infusion (5.5 micrograms/kg X min for 30 min) compared with that during saline infusion. These results indicate that D can induce a significant decline in plasma levels of ACTH, beta-lipotropin, and beta-endorphin, the major circulating peptides from the C-terminal part of proopiocortin, and suggest that opioid peptides may be involved in the control of the functional activity of pituitary-adrenocortical activity in man.

Adrenocorticotropic Hormone↗
PubMed1985

Effect of somatostatin on growth hormone and prolactin response to dermorphin in man.

The effects of iv somatostatin (somatotrophin release inhibiting factor (SRIF) on growth hormone (GH) and prolactin (Prl) response to dermorphin (D) were tested in 6 healthy men. In all subjects D induced a significant increase in GH and Prl levels, as expected. SRIF completely blocked the GH-releasing activity of D, whereas it only reduced the Prl-releasing activity. The results confirm that D is a potent stimulant for GH and Prl release in man, and furthermore demonstrate that the action of D on GH secretion can be completely overridden by SRIF.

Adult↗
PubMed1985

Opioid peptides. Conformational studies of dermorphin and its constitutive fragments by circular dichroism. IX.

Dermorphins are potent opiate-like heptapeptides which have been isolated from the skin of South American frogs. The Circular Dichroism spectra carried out on dermorphin (Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2), on the analogous [L-Ala2] dermorphin and on N-terminal fragments suggest that, in solution, the native molecule possesses a peculiar folded conformation responsible for its pharmacological activity. The presence of alanine in D configuration and of aminoacid residues possessing a high "beta-turn" potential, seems to be the main reason for such active conformation.

Amino Acid Sequence↗
PubMed1984

Dermorphin, a new opioid peptide, stimulates thyrotropin secretion in normal subjects.

The effect of a recently described, potent opioid peptide, dermorphin (DER), on TSH secretion in euthyroid subjects has been studied. DER infused at a rate of 5.5 micrograms/Kg/min for 30 min induced a significant increase in serum TSH concentration at 60, 90, and 120 min after the infusion was begun. Treatment with naloxone administered 30 min before the DER infusion with a bolus dose of 4 mg, followed by a constant infusion of 1 microgram/Kg/min for 150 min, prevented the rise in serum TSH. Naloxone administered alone did not induce any change in TSH concentration. The present findings suggest that DER has a stimulatory effect on TSH secretion, probably mediated by opioid receptors. These results, however, do not solve the question as to whether opioids have a physiological role in the control of pituitary TSH secretion.

Adolescent↗
PubMed1984

Structure-activity relationships for dermorphin-related tetrapeptides.

The opiate-like activity of six newly synthesized dermorphin-related tetrapeptides was determined in guinea pig ileum, mouse vas deferens and mouse tail-flick tests. Naloxone was a powerful antagonist of all compounds. Moreover, the biological activities of the compounds under examination were correlated in a statistically significant way to the lipophilic character of the C-terminal substituents and to an indicator variable taking into account the presence of an amidic group at the C-terminus.

Animals↗
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↗