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Endogenous and exogenous opiates are currently considered the drugs of choice for treating different kinds of pain. However, their prolonged use produces several adverse symptoms, and in addition, many forms of pain are resistant to any kind of therapy. Therefore, the discovery of compounds active towards μ-opioid receptors (MORs) by alternative pharmacological mechanisms could be of value for developing novel classes of analgesics. There is evidence that some unusual molecules can bind opioid receptors, albeit lacking some of the typical opioid pharmacophoric features. In particular, the recent discovery of a few compounds that showed agonist behavior even in the absence of the primary pharmacophore, namely a protonable amine, led to a rediscussion of the importance of ionic interactions in stabilizing the ligand–receptor complex and in activating signal transduction. Very recently, we synthesized a library of cyclic analogs of the endogenous, MOR-selective agonist endomorphin-1 (YPWF-NH2), containing a Gly5 bridge between Tyr1 and Phe4. The cyclopeptide c[YpwFG] showed good affinity and agonist behavior. This atypical MOR agonist does not have the protonable Tyr amine. In order to gain more information about plausible mechanisms of interaction between c[YpwFG] and the opioid receptor, we synthesized a selected set of derivatives containing different bridges between Tyr1 and Phe4, and tested their affinities towards μ-opioid receptors. We performed conformational analysis of the cyclopeptides by NMR spectroscopy and molecular dynamics, and investigated plausible, unprecedented modes of interaction with the MOR by molecular docking. The successive quantum mechanics/molecular mechanics investigation of the complexes obtained by the molecular docking procedure furnished a more detailed description of the binding mode and the electronic properties of the ligands. The comparison with the binding mode of the potent agonist JOM-6 seems to indicate that the cyclic endomorphin-1 analogs interact with the receptor by way of an alternative mechanism, still maintaining the ability to activate the receptor. [ABSTRACT FROM AUTHOR]

We previously described a novel endomorphin-1 analogue (Tyr-l-β-Pro-Trp-Phe-NH2; Endo1-β-Pro) more resistant to enzymatic hydrolysis than endomorphin-1 that acts as a μ-opioid receptor agonist. In this study we report that Endo1-β-Pro, s.c. injected in the mouse, is an effective antinociceptive agent in the tail flick (ED50=9.2 mg/kg) and acetic acid-induced abdominal constriction (ED50=1.2 mg/kg) tests. Moreover, s.c. Endo1-β-Pro significantly decreases, in the mouse, the gastrointestinal propulsion measured as transit of an orally administered charcoal meal (ED50=10.0 mg/kg). Subcutaneous β-funaltrexamine or a high dose of the μ1-opioid receptor-selective antagonist naloxonazine (50 mg/kg) prevents the antinociceptive and antitransit action of Endo1-β-Pro; moreover, these effects are partially blocked by i.c.v. naloxone or by i.p. naloxone methiodide, this latter does not readily cross the blood–brain barrier. On the contrary, the κ-opioid receptor antagonist nor-binaltorphimine or the δ-opioid receptor antagonist naltrindole are ineffective Thus, Endo1-β-Pro may act, preferentially, through central and peripheral μ2-opioid receptors to produce antinociception and to inhibit gastrointestinal transit. Endo1-β-Pro is among the first endomorphin-1 analogues showing antinociceptive activity after systemic administration. This compound will be extremely useful for exploring the pharmacological profile of endomorphins in vivo and confirms the potential therapeutic interest of endomorphin derivatives as novel analgesic agents. [Copyright &y& Elsevier]

Recent evidence highlighted the role of alpha(5)beta(1) integrin in angiogenesis and in regulating alpha(v)beta(3) integrin function. As a consequence, selective alpha(5)beta(1) integrin inhibitors or dual alpha(5)beta(1)/alpha(v)beta(3) integrin inhibitors are considered promising candidates for the development of cancer therapeutic agents. In this paper, we describe the synthesis and pharmacological characterization of a minilibrary of cyclotetrapeptide mimetics containing a PMRI Arg-Gly-Asp sequence. In particular, c[(R)-betaPhepsi(NHCO)Asppsi(NHCO)Gly-Arg] (3) displayed a good activity in inhibiting the alpha(v)beta(3) integrin-mediated cell adhesion of fibronectin or vitronectin, as well as the adhesion of fibronectin to the alpha(5)beta(1) integrin. Interestingly, the diastereomeric compound c[(S)-betaPhepsi(NHCO)Asppsi(NHCO)Gly-Arg] (2) maintained a good efficacy in inhibiting alpha(5)beta(1) integrin while gaining a certain selectivity over alpha(v)beta(3) integrin. These two integrin antagonists significantly inhibited bFGF-induced human endothelial cell tube formation at submicromolar concentrations. Conformational analysis and Molecular Docking calculations suggest that the different alpha(5)beta(1) versus alpha(v)beta(3) selectivity of 2 and 3 can be rationalized on the basis of the alternative display of the aromatic side chain adjacent to Asp.

Cyclic peptides have been often utilized as metabolically stable, conformationally restricted mimics of different kinds of biologically active peptides, including peptide antibiotics, endogenous opioid peptides, integrin inhibitors, peptide hormones, anticancer peptides, and so on. And in particular, cyclic compounds which can mimic important secondary structure elements such as beta-turns are of outstanding importance. Since greater chemical and structural diversity are primary features to pursue for finding novel leads for pharmacological and biotechnological applications, we explored the potential utility of the retro-inverso modification. We introduced this modification into the sequence of 13-membered cyclotetrapeptides, which can be regarded as easily available, conformationally stable analogs of cyclotetrapeptides composed of all alpha-residues. In this paper we describe the synthesis of a selected mini-library of partially modified retro-inverso cyclic peptides as conformationally homogeneous scaffolds for medicinal chemistry applications. The different compounds have been obtained by simple scramble of the same residues. Finally, we discuss the conformational features of such molecules as turn mimics. The comparison suggests that the retro-inverso modification allows a higher degree of three-dimensional diversity than normal peptides.

The conformations of all stereoisomers of PMRI cyclotetrapeptide mimetics 1-8 are essentially determined by the predisposition of the diamine to stabilize beta-turns. The peptide mimetics can be regarded as 3D scaffolds for designing molecules with a predictable display of the pharmacophores. We used the models for testing novel RGD analogues as alpha(v)beta(3)-integrin receptor antagonists.

The allylic amination of acetates and carbonates affords dehydro-beta-aminoesters, which are useful precursors of biologically active compounds. The uncatalyzed reaction proceeds via a S(N)2' mechanism. On the other hand, under palladium-catalyzed conditions, the reaction shows a strong solvent-dependent regiocontrol, affording exclusively one of the two possible regioisomers with complete transfer of chirality from the substrates to the products.

Small constrained non-peptidic molecules consisting of a polyfunctionalized rigid core, carrying appendages corresponding to arginine and aspartic acid side chains, have been recently reported to be promising for drug development. In this work, the 5,6-dihydropyridin-2-one was envisaged as a scaffold to turn into potential integrin ligands, introducing a carboxylic acid and a basic appendage. The synthesis and the antiadhesion activity of a small library of peptidomimetics capable to recognize alpha(v)beta(3) and alpha(5)beta(1) integrins has been herein reported.

In this paper, we describe the synthesis of a selected library of heterochiral d-Pro-containing RGD-peptidomimetics (RpD) and we investigate the biological activity as inhibitors of fibronectin adhesion to SK-MEL-24 tumor cells. In particular, peptides 4 and 8 showed an IC(50) in the 10(-8)M range. Despite the linear structure, the peptides tend to adopt a folded conformation in a polar environment.

Unprecedented classes of four- and five-membered hydroxyl-spiro-beta-lactams and hydroxyl-azido-beta-lactams were prepared via regioselective ring opening of hydroxyl-epoxides. The potential of these particular beta-lactams as biologically active compounds has been confirmed by the results obtained in ACAT inhibition assays.

The stereoselective anti SN2' attack of NaN3 to 3-alkenyl-3-bromo-azetidin-2-ones gave a mixture of diastereomeric azides in fast equilibrium. The [3,3]-sigmatropic rearrangement of allylic azides occurred with complete stereocontrol, allowing the equilibrium to be directed preferentially toward the (E)- or (Z)-isomer, useful precursors of 3(2'-amino)-beta-lactams. [reaction: see text]

An ultimate and general model describing the interaction between opioid ligands and mu-opioid receptors is not available yet, so the mode of action of atypical peptide analogues or peptidomimetics is worthy of investigation. In this context, the peptide c[-Tyr-d-Pro-d-Trp-Phe-Gly-] was observed to act as an agonist toward mu-opioid receptors with appreciable potency, albeit deprived of a protonable nitrogen. This compound was synthesized as a member of a library of diastereo- or enantiomeric cyclic peptides based on the sequence of endomorphin-1, aiming to obtain lipophilic peptide ligands active at the mu-opioid receptors, having good performances in terms of resistance to enzymatic degradation and permeation of biological barriers.

Peptide carbamates containing the sequence H-Pro-Trp-PheNH2 showed in CDCl3 restricted conformations stabilized by the presence of a gamma-turn. To test the reliability of the peptides as endomorphin conformational models, we measured the affinities for mu-receptors labelled with [3H]-DAMGO. In particular, Cbz-Pro-Trp-PheNH2 displayed a nanomolar affinity.

The enantiomer of endomorphin-1 (Tyr-Pro-Trp-PheNH2) and the analogues containing (S)- or (R)-beta-proline have been synthesized, and their affinities towards mu-opioid receptors have been measured. As expected, the incubations of the different peptides with some commercially available enzymes showed that the presence of D-residues gave strong resistance towards digestion. The presence of beta-proline alone is sufficient to confer good resistance against the hydrolysis of the biologically strategic Pro-Trp bond.

In this paper we describe the synthesis and affinity toward the mu-opioid receptor of some tetrapeptides obtained from endomorphin-1, H-Tyr-Pro-Trp-Phe-NH(2) (1), by substituting each amino acid in turn with its homologue. The ability to bind mu-opioid receptors depends on the beta-amino acid, and in particular 4, which contains beta-L-Pro, has a K(I) in the nanomolar range. The peptides 4 and 5 are significantly more resistant to enzymatic hydrolysis than 1. The same compounds, as well as the mu-opioid receptor agonist DAMGO, produced a concentration-dependent inhibition of forskolin-stimulated cyclic AMP formation, thus behaving as mu-opioid agonists. These features suggest that this novel class of endomorphin-1 analogues may represent suitable candidates for the in vivo investigation as potential mu-opioid receptor agonists.