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Equilibri di complesso-formazione tra ione rame e proteina prionica: studio su peptidi modello
No full textIL GIOCO MOLECOLARE TRA DRUG DISCOVERY E CHEMICAL BIOLOGY
Full text linkLa chemical biology è una disciplina vicina alla chimica farmaceutica strettamente connessa
al processo di drug discovery mediante uno scambio di ruolo di inibitori/ligandi e probe
molecolari. In tre esempi di applicazione della chemical biology-drug discovery vengono
illustrati i linker per la bioconiugazione, le sonde fluorescenti in studi di interazione farmacorecettore
cellulare (target engagement) e l’indagine proteomica dei meccanismi biologici
d’azione di inibitori specifici
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
Long-lasting antinociceptive spinal effects in primates of the novel nociceptin/orphanin FQ receptor agonist UFP-112
Full text linkChemical modifications of nociceptin/orphanin FQ (N/OFQ) peptide that result in increased potency and resistance to degradation have recently lead to the discovery of [(pF)Phe(4)Aib(7)Arg(14)Lys(15)]N/OFQ-NH(2) (UFP-112), a novel N/OFQ peptide (NOP) receptor agonist. The aim of this study was to investigate the pharmacological profile of intrathecally administered UFP-112 in monkeys under different behavioral assays. Intrathecal UFP-112 (1-10 nmol) dose-dependently produced antinociception against an acute noxious stimulus (50 degrees C water) and capsaicin-induced thermal hyperalgesia. Intrathecal UFP-112-induced antinociception could be reversed by a NOP receptor antagonist, J-113397 (0.1mg/kg), but not by a classic opioid receptor antagonist, naltrexone (0.03 mg/kg). Like intrathecal morphine, UFP-112 produced antinociception in two primate pain models with a similar magnitude of effectiveness and a similar duration of action that last for 4-5h. Unlike intrathecal morphine, UFP-112 did not produce itch/scratching responses. In addition, intrathecal inactive doses of UFP-112 and morphine produced significant antinociceptive effects when given in combination without increasing scratching responses. These results demonstrated that intrathecal UFP-112 produced long-lasting morphine-comparable antinociceptive effects without potential itch side effect. This study is the first to provide functional evidence that selective NOP receptor agonists such as UFP-112 alone or in conjunction with morphine may improve the quality of spinal analgesia. Copyright 2009 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved
Supraspinal and spinal effects of [Phe(1)psi(CH2-NH)Gly(2)]-nociceptin(1-13)-NH2 on nociception in the rat
No full textA new derivative of the neuropeptide nociceptin (NC) has recently been
developed. This molecule, the pseudopeptide [PhelY(CI-I2NH)Gly2]-
nociceptin( I-13)-NHZ was found to antagonize NC inhibitory effects in peripheral
smooth muscle preparations in vitro. However, contrasting results have appeared
as regards its pharmacodynamic profile in the CNS. Here, we investigated the
pseudopeptide effects, in vivo, on nociceptive responses in the rat. IphelY(CH2-
NH)Gly2]-nociceptin( 1 - 13)~NH2 was administered intracerebroventricularly
(icv.) or intrathecally (i.t.) (alone or in combination with NC), and tail-flick
latencies (TFL) to radiant heat were assessed. I.c.v. [PhelY(CHzNH)Gly2]-
nociceptin( l-13)-NH2 (I-10 nmoYrat) caused a short-lasting decrease (5 min) of
TFL and did not antagonize the threshold lowering effect of i.c.v. NC (1 nmol/rat).
At the spinal level, the i.t. administration (0.2-10 nmol/rat) of [PhelY(CH2-
NH)Gly2]-nociceptin( 1 - 13)~NH2 produced a dose-dependent and long-lasting
antinociceptive effect that was not modified by the administration of a high dose
(30 nmol/rat i.t.) of the opioid antagonist naloxone. The i.t. co-administration of
the pseudopeptide (10 nmol/rat) did not block the antinociceptive effect of i.t. NC
(10 nmol/rat). These data indicate that the pseudopeptide behaves as an NC
agonist at supraspinal and spinal levels in the rat tail-flick test of nociception.
These different profiles in the periphery and the CNS could suggest differences
between central and peripheral NC receptor/s and provide a basis for further
development of antagonist molecules suitable for their characterization
Studies of the cardiovascular effects of nociceptin and related peptides
No full textNociceptin, a novel opioid peptide, and its ORL1 receptor share structural similarities with other opioid ligands and receptors. Although
NC exerts evident cardiovascular effects at a central and peripheral level, its role in homeostatic mechanisms and disease states are just
beginning to be understood, as only recently selective receptor antagonists became available. In this review, some of the new observations
regarding the cardiovascular actions of NC, related peptides and newly synthesized receptor antagonists are discussed
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
Pharmacology of nociceptin and its receptor: a novel therapeutic target
No full textNociceptin (NC), alias Orphanin FQ, has been recently identified as the endogenous ligand of the opioid receptor-like 1 receptor (OP(4)). This new NC/OP(4) receptor system belongs to the opioid family and has been characterized pharmacologically with functional and binding assays on native (mouse, rat, guinea-pig) and recombinant (human) receptors, by using specific and selective agonists (NC, NC(1 - 13)NH(2)) and a pure and competitive antagonist, [Nphe(1)]NC(1 - 13)NH(2). The similar order of potency of agonists and affinity values of the antagonist indicate that the same receptor is present in the four species. OP(4) is expressed in neurons, where it reduces activation of adenylyl cyclase and Ca(2+) channels while activating K(+) channels in a manner similar to opioids. In this way, OP(4) mediates inhibitory effects in the autonomic nervous system, but its activities in the central nervous system can be either similar or opposite to those of opioids. In vivo experiments have demonstrated that NC modulates a variety of biological functions ranging from nociception to food intake, from memory processes to cardiovascular and renal functions, from spontaneous locomotor activity to gastrointestinal motility, from anxiety to the control of neurotransmitter release at peripheral and central sites. These actions have been demonstrated using NC and various pharmacological tools, as antisense oligonucleotides targeting OP(4) or the peptide precursor genes, antibodies against NC, an OP(4) receptor selective antagonist and with data obtained from animals in which the receptor or the peptide precursor genes were knocked out. These new advances have contributed to better understanding of the pathophysiological role of the NC/OP(4) system, and ultimately will help to identify the therapeutic potential of new OP(4) receptor ligands
Medicinal Chemistry, Pharmacology, and Biological Actions of Peptide Ligands Selective for the Nociceptin/Orphanin FQ Receptor
No full textNociceptin/orphanin FQ (N/OFQ; FGGFTGARKSARKLANQ) was identified via reverse pharmacology strategies as the endogenous ligand of a previously orphan GPCR now referred to as N/OFQ peptide (NOP) receptor. The N/OFQ – NOP receptor system is widely distributed in the nervous system where it modulates several different biological functions. Structure relationship studies performed on the N/OFQ sequence allowed to generate NOP selective ligands encompassing full and partial agonist as well as pure antagonist activity, to increase their potency, metabolic stability, and in vivo duration of action. These peptide NOP ligands were used to investigate the consequences of NOP receptor activation and block thus suggesting the possible therapeutic indications of drugs interacting with this receptor. Evidence coming from these studies, together with findings obtained with knockout animals and non peptide NOP ligands, suggests that the most promising indications for NOP antagonists are depression and Parkinson disease and for agonists anxiety, drug abuse, cough, and pain (after spinal administration). In addition, clinical studies demonstrated that intravesical instillation of N/OFQ elicits beneficial effects in patients with overactive bladder
[Nphe(1),Arg(14),Lys(15)]N/OFQ-NH2 is a competitive antagonist of NOP receptors in the periaqueductal gray
No full textNociceptin/orphanin FQ (N/OFQ) and N/OFQ peptide (NOP) receptors are implicated in many physiological functions including pain
regulation. This study quantitatively investigated the interaction of a novel NOP receptor antagonist, UFP-101 ([Nphe1,Arg14,Lys15]N/OFQNH2),
with N/OFQ in the ventrolateral periaqueductal gray, a crucial midbrain area for pain regulation. N/OFQ concentration-dependently
activated G-protein coupled inwardly rectifying K+ (GIRK) channels in ventrolateral neurons of periaqueductal gray slices. UFP-101
antagonized N/OFQ-induced GIRK channel activation in a concentration-dependent manner and produced a parallel shift of the
concentration-response curve of N/OFQ. The pA2 value estimated from Schild plot is 6.92T0.06. At concentrations up to 1 AM, UFP-101
had no effect on membrane current per se and did not affect the GIRK current activated by [d-Ala2, N-Me-Phe4, Gly-ol5]-enkephalin, a Aopioid
receptor agonist. It is concluded that UFP-101 is a potent and competitive peptide antagonist of NOP receptors that mediate GIRK
channel activation in ventrolateral periaqueductal gray neurons
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