Synthesis and Analysis of the Conformational Preferences of 5-Aminomethyloxazolidine-2,4-dione Scaffolds: First Examples of \u3b22- and \u3b22, 2-Homo-Freidinger Lactam Analogues

Constrained peptidomimetic scaffolds are of considerable interest for the design of therapeutically useful analogues of bioactive peptides. We present the single-step cyclization of (S)- or (R)-\u3b1-hydroxy-\u3b22- or \u3b1-substituted-\u3b1-hydroxy-\u3b22, 2-amino acids already incorporated within oligopeptides to 5-aminomethyl-oxazolidine-2,4-dione (Amo) rings. These scaffolds can be regarded as unprecedented \u3b22- or \u3b22, 2-homo-Freidinger lactam analogues, and can be equipped with a proteinogenic side chain at each residue. In a biomimetic environment, Amo rings act as inducers of extended, semi-bent or folded geometries, depending on the relative stereochemistry and the presence of \u3b1-substituents

Expedient synthesis of pseudo-Pro-containing peptides: Towards constrained peptidomimetics and foldamers

The reaction of sulfonyl peptides containing l- or d-configured Ser or Thr with bis(succinimidyl) carbonate in the presence of a catalytic amount of a base affords, in solution or in the solid phase, the corresponding peptides with one or two, consecutive or alternate oxazolidin-2-ones (Oxd). The Oxd ring can be regarded to as a pseudo-Pro with an exclusively trans conformation of the preceding peptide bond; homochiral Oxd-containing peptides adopt extended conformations, while the presence of a d-configured Oxd favours folded conformations. © The Royal Society of Chemistry 2012

Opioid activity profiles of oversimplified peptides lacking in the protonable N-terminus

Recently, we described cyclopeptide opioid agonists containing the D-Trp-Phe sequence. To expand the scope of this atypical pharmacophore, we tested the activity profiles of the linear peptides Ac-Xaa-Phe-Yaa (Xaa = L/D-Trp, D-His/Lys/Arg; Yaa = H, GlyNH2). Ac-D-Trp-PheNH2 appeared to be the minimal binding sequence, while Ac-D-Trp-Phe-GlyNH 2 emerged as the first noncationizable short peptide (partial) agonist with high \u3bc-opioid receptor affinity and selectivity. Conformational analysis suggested that 5 adopts in solution a \u3b2-turn conformation. \ua9 2012 American Chemical Society

In-Peptide Synthesis of Imidazolidin-2-one Scaffolds, Equippable with Proteinogenic or Taggable/Linkable Side Chains, General Promoters of Unusual Secondary Structures

Peptidomimetics containing (S)- or (R)-imidazolidin-2-one-4- carboxylate (Imi) have been obtained by the expedient in-peptide cyclization of (S)- or (R)-\u3b1,\u3b2-diaminopropionic acid (Dap) residues. These Imi scaffolds behave as proline analogues characterized by a flat structure and a transrestricted geometry of the preceding peptide bond and induce well-defined secondary structures in a biomimetic environment. While (S)-Imi peptides adopted a \u3b3\u2032-turn conformation, (R)-Imi induced the contemporary formation of a \u3b3-turn and a rare 11-membered H-bonded structure in the 2\u21924 opposite direction of the sequence, identified as a \u3b5-turn. In order to exploit these Imi scaffolds as general promoters of unusual secondary structures, proteinaceous side chains have been introduced at the N1 position of the five-membered ring, potentially mimicking any residues. Finally, the Imi rings have been equipped with unnatural side chains or with functionalized substituents, which can be utilized as linkers to chemoselectively bind the Imi-peptides onto nanoparticles, biomaterials, or diagnostic probes

In-peptide synthesis of di-oxazolidinone and dehydroamino acid-oxazolidinone motifs as \u3b2-turn inducers

Small and easy-to-do mimetics of \u3b2-turns are of great interest to interfere with protein-protein recognition events mediated by \u3b2-turn recognition motifs. We propose a straightforward procedure for constraining the conformation of tetrapeptides lacking a pre-formed scaffold. According to the stereochemistry array, N-Ts tetrapeptides including Thr or PhSer (phenylserine) at the positions 2 or 3 gave rise in a single step to the sequences Oxd 2-Oxd3 or \u394Abu2-Oxd3 (Oxd, oxazolidin-2-one; \u394Abu, 2,3-dehydro-2-aminobutyric). These pseudo-Pro residues displayed highly constrained, and \u3c7 dihedral angles, and induced clear \u3b2-turns or inverse turns of type I or II, as determined by extensive spectroscopic and computational analyses. \ua9 The Royal Society of Chemistry 2013

Functional Selectivity and Antinociceptive Effects of a Novel KOPr Agonist

Kappa opioid receptor (KOPr) agonists represent alternative analgesics for their low abuse potential, although relevant adverse effects have limited their clinical use. Functionally selective KOPr agonists may activate, in a pathway-specific manner, G protein-mediated signaling, that produces antinociception, over \u3b2-arrestin 2-dependent induction of p38MAPK, which preferentially contributes to adverse effects. Thus, functionally selective KOPr agonists biased toward G protein-coupled intracellular signaling over \u3b2-arrestin-2-mediated pathways may be considered candidate therapeutics possibly devoid of many of the typical adverse effects elicited by classic KOPr agonists. Nonetheless, the potential utility of functionally selective agonists at opioid receptors is still highly debated; therefore, further studies are necessary to fully understand whether it will be possible to develop more effective and safer analgesics by exploiting functional selectivity at KOPr. In the present study we investigated in vitro functional selectivity and in vivo antinociceptive effects of LOR17, a novel KOPr selective peptidic agonist that we synthesized. LOR17-mediated effects on adenylyl cyclase inhibition, ERK1/2, p38MAPK phosphorylation, and astrocyte cell proliferation were studied in HEK-293 cells expressing hKOPr, U87-MG glioblastoma cells, and primary human astrocytes; biased agonism was investigated via cAMP ELISA and \u3b2-arrestin 2 recruitment assays. Antinociception and antihypersensitivity were assessed in mice via warm-water tail-withdrawal test, intraperitoneal acid-induced writhing, and a model of oxaliplatin-induced neuropathic cold hypersensitivity. Effects of LOR17 on locomotor activity, exploratory activity, and forced-swim behavior were also assayed. We found that LOR17 is a selective, G protein biased KOPr agonist that inhibits adenylyl cyclase and activates early-phase ERK1/2 phosphorylation. Conversely to classic KOPr agonists as U50,488, LOR17 neither induces p38MAPK phosphorylation nor increases KOPr-dependent, p38MAPK-mediated cell proliferation in astrocytes. Moreover, LOR17 counteracts, in a concentration-dependent manner, U50,488-induced p38MAPK phosphorylation and astrocyte cell proliferation. Both U50,488 and LOR17 display potent antinociception in models of acute nociception, whereas LOR17 counteracts oxaliplatin-induced thermal hypersensitivity better than U50,488, and it is effective after single or repeated s.c. administration. LOR17 administered at a dose that fully alleviated oxaliplatin-induced thermal hypersensitivity did not alter motor coordination, locomotor and exploratory activities nor induced pro-depressant-like behavior. LOR17, therefore, may emerge as a novel KOPr agonist displaying functional selectivity toward G protein signaling and eliciting antinociceptive/antihypersensitivity effects in different animal models, including oxaliplatin-induced neuropathy

Integrin-Targeting Dye-Doped PEG-Shell/Silica-Core Nanoparticles Mimicking the Proapoptotic Smac/DIABLO Protein

Cancer cells demonstrate elevated expression levels of the inhibitor of apoptosis proteins (IAPs), contributing to tumor cell survival, disease progression, chemo-resistance, and poor prognosis. Smac/DIABLO is a mitochondrial protein that promotes apoptosis by neutralizing members of the IAP family. Herein, we describe the preparation and in vitro validation of a synthetic mimic of Smac/DIABLO, based on fluorescent polyethylene glycol (PEG)-coated silica-core nanoparticles (NPs) carrying a Smac/DIABLO-derived pro-apoptotic peptide and a tumor-homing integrin peptide ligand. At low \u3bcM concentration, the NPs showed significant toxicity towards A549, U373, and HeLa cancer cells and modest toxicity towards other integrin-expressing cells, correlated with integrin-mediated cell uptake and consequent highly increased levels of apoptotic activity, without perturbing cells not expressing the \u3b15 integrin subunit

Grasp It Loudly! Supporting Actions with Semantically Congruent Spoken Action Words

Evidence for cross-talk between motor and language brain structures has accumulated over the past several years. However, while a significant amount of research has focused on the interaction between language perception and action, little attention has been paid to the potential impact of language production on overt motor behaviour

Ring size in cyclic endomorphin-2 analogs modulates receptor binding affinity and selectivity

The study reports the solid-phase synthesis and biological evaluation of a series of new side chain-to-side chain cyclized opioid peptide analogs of the general structure Tyr-[D-Xaa-Phe-Phe-Asp]NH2, where Xaa = Lys (1), Orn (2), Dab (3), or Dap (4) (Dab = 2,4-diaminobutyric acid, Dap = 2,3-diaminopropionic acid), containing 17- to 14-membered rings. The influence of the ring size on binding to the MOP, DOP and KOP opioid receptors was studied. In general, the reduction of the size of the macrocyclic ring increased the selectivity for the MOP receptor. The cyclopeptide incorporating Xaa = Lys displayed subnanomolar MOP affinity but modest selectivity over the KOP receptor, while the analog with the Orn residue showed increased affinity and selectivity for MOP. The analog with Dab was a weak MOP agonist and did not bind to the other two opioid receptors. Finally, the peptide with Xaa = Dap was completely MOP receptor-selective with subnanomolar affinity. Interestingly, the deletion of one Phe residue from 1 led to the 14-membered Tyr-c[D-Lys-Phe-Asp]NH2 (5), a potent and selective MOP receptor ligand. The in vitro potencies of the new analogs were determined in a calcium mobilization assay performed in Chinese Hamster Ovary (CHO) cells expressing human recombinant opioid receptors and chimeric G proteins. A good correlation between binding and the functional test results was observed. The influence of the ring size, solid support and the N-terminal protecting group on the formation of cyclodimers was studied

Esmethadone (REL-1017) and Other Uncompetitive NMDAR Channel Blockers May Improve Mood Disorders via Modulation of Synaptic Kinase-Mediated Signaling

This article presents a mechanism of action hypothesis to explain the rapid antidepressant effects of esmethadone (REL-1017) and other uncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonists and presents a corresponding mechanism of disease hypothesis for major depressive disorder (MDD). Esmethadone and other uncompetitive NMDAR antagonists may restore physiological neural plasticity in animal models of depressive-like behavior and in patients with MDD via preferential tonic block of pathologically hyperactive GluN2D subtypes. Tonic Ca2+ currents via GluN2D subtypes regulate the homeostatic availability of synaptic proteins. MDD and depressive behaviors may be determined by reduced homeostatic availability of synaptic proteins, due to upregulated tonic Ca2+ currents through GluN2D subtypes. The preferential activity of low-potency NMDAR antagonists for GluN2D subtypes may explain their rapid antidepressant effects in the absence of dissociative side effects