1,721,229 research outputs found
Antagonism in opioid peptides: The role of conformation
No full textThe availability of new, highly selective antagonists, in the field of opioid peptides and of other pain peptides, is important both for a better understanding of the interaction of the receptors with their ligands and for their practical relevance. The design of antagonists is not obvious even when the essential features of agonists are well known. In this review we have examined the main aspects of the problem using, as leading criteria two theoretical models of antagonism and the subdivision of opioid peptides into two functional domains. The main causes of antagonism have been integrated in two very general models: one, referred to as the participation model, attributes antagonism to the lack, with respect to the parent agonist, of an essential group, whereas another model, attributes antagonism to the misfit of the molecule inside the receptor. The second criterion is the division of the structure of peptide hormones, originally put forward by Robert Schwyzer, in two functional domains, the message domain, which is responsible of the larger part of the binding affinity of opioid agonists, and an address domain, which dictates most of the peptide specificity. The most significant achievements in the design of opioid antagonists are classified according to the relative importance of chemical constitution, conformation and chirality. © 2004 Bentham Science Publishers Ltd
The effects of dermorphin on the endocrine system in man
No full textThis 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 μg/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. © 1985
Effect of somatostatin on growth hormone and prolactin response to dermorphin in man
No full textThe 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
Supramolecular aggregates comprising maleimido cores
No full textThe invention relates to a supramolecular aggregate of formula (VI) wherein A is an active substance, and X1, X2, X3 and X4, independently to each other, are a moiety of Formula (I) containing a maleimido functionalization and at least one among X1, X2, X3 and X4 is present in Formula (VI). In a preferred embodiment the maleimido-funzionalized core is PWT2. The supra-molecular aggregate can be used in the field of drugs, vaccines, as ligands for GPCR, i.e. agonists as well as antagonist, as antibiotics and as diagnostics eventually in complex with radionuclides
Peptides and proteins in a confined environment: NMR spectra at natural isotopic abundance
No full textConfinement of proteins and peptides in a small inert space mimics the natural environment of the cell, allowing structural studies in conditions that stabilize folded conformations. We have previously shown that confinement in polyacrylamide gels (PAGs) is sufficient to induce a change in the viscosity of the aqueous solution without changing the composition and temperature of the solvent. The main limitation of a PAG to run NMR experiments in a confined environment is the need for labelling the peptides. Here we report the use of the agarose gel to run the NMR spectra of proteins and peptides. We show that agarose gels are completely transparent in NMR experiments, relieving the need for labelling. Although it is necessary to expose biomolecules to fairly high temperatures during sample preparation, we believe that this is not generally an obstacle to the study of peptides, and found that the method is also compatible with temperature-resistant proteins. The mesh of agarose gels is too wide for direct effects of confinement on the stability of proteins but confinement can be easily exploited to interact the proteins with other reagents, including crowding macromolecules that can eventually lead to fold stabilization. The use of these gels is ideally suited for low-temperature studies; we show that a very flexible peptide at subzero temperatures is stabilized into a well-folded conformation
Opioid peptides. Analgesic activity of potent dermorphin tetrapeptides. VI.
No full textBy 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 degradatio
The novel delta opioid receptor agonist UFP-512 dually modulates motor activity in hemiparkinsonian rats via control of the nigro-thalamic pathway
No full textThe present study aimed to characterize the ability
of the novel delta opioid peptide (DOP) receptor agonist H-Dmt-
Tic-NH-CH(CH2–COOH)-Bid (UFP-512) to attenuate motor deficits
in 6-hydroxydopamine (6-OHDA) hemilesioned rats. Lower
doses (0.1–10 g/kg) of UFP-512 administered systemically
(i.p.) stimulated stepping activity in the drag test and overall
gait abilities in the rotarod test whereas higher doses (100–
1000 g/kg) were ineffective or even worsened Parkinsonism.
Microdialysis coupled to an akinesia test (bar test) was then
used to determine the circuitry involved in the motor actions
of UFP-512. An antiakinetic dose of UFP-512 (10 g/kg) decreased
GABA in globus pallidus (GP) as well as GABA and
glutamate (GLU) release in substantia nigra reticulata (SNr).
On the other hand, a pro-akinetic dose (1000 g/kg) of UFP-
512 increased pallidal GABA, simultaneously producing a decrease
in GABA and an increase in nigral GLU release. Moreover,
to test the hypothesis that changes in motor behavior
were associated with changes in nigro–thalamic transmission,
amino acid release in ventromedial thalamus (VMTh, a target of
nigro–thalamic GABAergic projections) was also measured.
The anti-akinetic dose of UFP-512 reduced GABA and increased
thalamic GLU release while the pro-akinetic dose increased
GABA without affecting thalamic GLU release. Finally, regional
microinjections were performed to investigate the brain areas
involved in motor actions of UFP-512. UFP-512 microinjections
into GP increased akinesia whereas UFP-512 microinjections
into SNr reduced akinesia. Furthermore, the selective DOP receptor
antagonist naltrindole (NTD) increased akinesia when
injected into either area, GP being more sensitive. We conclude
that UFP-512, depending on dose, improves or worsens motor
activity in hemiparkinsonian rats by acting differentially as a
DOP receptor agonist in SNr and a DOP receptor antagonist in
GP, ultimately decreasing or increasing the activity of nigro–
thalamic GABAergc output neurons, respectively
Tritiation of delta opioid-receptor selective antagonist dipeptide ligands with extraordinary affinity containing 2 ', 6 ' dimethyltyrosine
No full textRecently a new class of ~ opioid antagonists has been discovered by using Tyr-Tic sequence.
The substitution of Tyr 1 by Dmt resulted in a new analogue (H-Dmt-Tic-OH) with enhanced
affinity and selectivity. Because of its excellent property we chose it for labelling with tritium.
At the same time peptides containing Tic at position 2 undergo spontaneous diketopiperazine
formation in some solvents, and they lose some of their binding ability. To avoid this unwanted
side- reaction we synthetized the N-methylated analogue (N,N(Me)2- Dmt-Tic-OH), and it was
more stable under storage condition, but 5 affinity declined moderately. On the basis of this
information we prepared diiodinated analogues of these dipeptides. Catalytic dehalotritiation of
precursors resulted in tritiated peptides. High specific radioactivity, 44.67 Ci/mmol with
[3H]Dmt-Tic-OH and 59.88 Ci/mmol with N,N(Me)2-[ 3H]Dmt-Tic-OH were achieved
Pharmacological studies of a series of dermorphin related tetrapeptides
No full textThe 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
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