Biomedical subjects
Publications and source records attributed to R Tomatis.
We describe the synthesis and preliminary in vitro and in vivo pharmacological tests of five endothiotetrapeptide analogues of the opioid heptapeptide dermorphin H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser.-NH2. The modification obtained by substituting Phet for Phe3 or Glyt for Gly4 provided further analogues with significant opioid activity.
Pharmacological activity in vitro and in vivo of 17 pentapeptide analogs of dermorphin (opioid heptapeptide) are reported. Substitutions of the Tyr5 residue afford dermorphin related pentapeptides which are likely to discriminate between mu- and delta-receptors.
Two new related heptapeptides (dermorphins) with potent central and peripheral opiate-like activity have been isolated from the skin of South American frogs, and have been chemically characterized as H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2 (dermorphin) and H-Tyr-D-Ala-Phe-Gly-Tyr-Hyp-Ser-NH2 (Hyp6-dermorphin). The response of GH to infusion of a synthetic dermorphin (5.5 micrograms/kg/min for 30 min) was studied in 9 healthy men. Dermorphin (D) significantly increased plasma growth hormone (GH) concentrations. The GH response to D was blunted by prior administration of naloxone, suggesting that D interacts with mu-type opiate receptors. However, the evaluation of the physiological significance of D-induced GH release in humans requires further study.
Dermorphins (D) are heptapeptides (H-Tyr-D-Ala-Phe-Gly-Tyr-X-Ser-NH2; X, Pro or Hyp) with powerful central and peripheral opiate-like activity, originally isolated from the skin of South American frogs. To study the effect of a synthetic D on PRL secretion in man, either D (5.5 micrograms/kg . min for 30 min) or D-placebo (0.9% saline) infusion over 30 min was administered iv in random sequence to 11 volunteers (6 women and 5 men). In all the subjects, D induced a significant increase in the levels of PRL, more consistently in women than in men. To investigate whether the increase in PRL was due to the opiate agonist properties of D, the study was repeated in the same subjects during naloxone infusion. The PRL response to D was completely suppressed, suggesting that the peptide exerts its effect on PRL release via an opiate receptor stimulation of the mu-type. These data allow us to conclude that D may affect PRL release in humans; however, further investigation is necessary before any physiological significance might be attributed to D in man.
This study was designed to investigate the effect of dermorphin (D), a new synthetic potent opiate-like peptide (H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2), on PRA, plasma aldosterone (PA), plasma cortisol (PC), and plasma ACTH levels in normal men. D infusion (5.5 micrograms/kg X min for 30 min) significantly increased PRA (P less than 0.01) and decreased PC levels (P less than 0.02). D produced a small decrease in ACTH and a small increase in PA. Pretreatment with the opioid receptor antagonist naloxone (N) blunted the D-induced PRA increase and completely prevented the D-induced PC decrease, but enhanced PC 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, increases PRA levels, perhaps via activation of the sympathetic nervous system, providing evidence that opioid peptides may exert an influence on renin secretion; and 2) D suppresses PC levels, perhaps by affecting ACTH secretion, corroborating previous observations that opioid peptides might affect the function of the pituitary-adrenocortical axis.
The preliminary pharmacological activity pattern in guinea pig ileum and mouse vas deferens bioassays of five dermorphin related tetrapeptides is reported. The biological activities of the compounds under examination appear to be correlated in a statistically significant way to the lipophilic character of the C-terminal substituents.
We describe the synthesis and preliminary in vitro and in vivo pharmacological tests of six [beta-Ala4]tetrapeptides analogs of the opioid heptapeptide dermorphin H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2. The modification obtained by substituting beta-Ala4 for Gly4 provided further analogues with significant opioid activity.
By employing the mouse tail-flick assay the analgesic activity of selected dermorphin tetrapeptides was assessed. The remarkable differences in potency exhibited by peptides after i.c.v. (500-1000 times higher than morphine) and s.c. (nearly comparable to morphine) administration are probably due to peptidase degradation.
The activity pattern of 8 dermorphin related tetrapeptides was determined in guinea-pig ileum and mouse vas deferens bioassays. Naloxone was a powerful antagonist of all compounds in both preparations. Moreover the biological activities of the test compounds were correlated in a statistically significant way to the lipophilic character of the C-terminal substituents.
The synthesis and preliminary pharmacological in vitro of seventeen pentapeptide analogs of the opioid peptide dermorphin are reported. Substitution at residue Tyr5 and/or modification of C-terminal are generally well tolerated.
H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2 (demorphin), and opiate-like peptide, and tri-, tetra-, penta- and hexapeptide-amide analogs, were synthesized by conventional methods in solution, to determine the minimum peptide chain-length, required for analgesic activity.
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.
Preliminary pharmacological data and the characterization of sixteen synthetic tetrapeptide-amide analogs of dermorphin (opioid heptapeptide) are reported. N,N-dialkylamides displayed reduced or no activity; on the contrary, derivatization of H-Tyr-D-Ala-Phe-Gly-OH C-terminus by suitable amide moieties (1-adamantanamine, 1-adamantane-methylamino, or D-alpha-methylbenzylamine) produced potent analogues with peripheral and central opioid activities comparable to, or higher than those of dermorphins.
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The preliminary pharmacological data on synthetic peptides related to dermorphin (opiate-heptapeptide) are reported. The tetrapeptide, corresponding to the N-terminal sequence of dermorphin is a minimum requirement for significant opiate-activity in vitro.
The synthesis and pharmacological activity of Leu-enkephalins carrying a free or substituted carboxymethyl group at glycine-2-nitrogen are described.
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