Rational Approach to the Design of Bioactive Peptidomimetics: Recent Developments in Opioid Agonist Peptides

Opioid Receptor Activity and Analgesic Potency of DPDPE Peptide Analogues Containing a Xylene Bridge

“…4 Met-Enkephalin and Leu-enkephalin are linear endogenous pentapeptides with high affinity for DOP regulating human nociception; numerous structural modifications have been explored during the last years to investigate the structure− activity relationships (SAR) and to improve their selectivity; 5,6 H-Tyr-c[D-Pen-Gly-Phe-D-Pen]-OH (DPDPE) is the first synthetic prototype of highly selective constrained cyclic peptide for this receptor (Figure 1). 7 DPDPE is employed as radiolabeled δ receptor full agonist in the opioid binding assays due to its resistance to proteolytic degradation and permeability to the blood−brain barrier (BBB). 8 The X-ray crystal structure of DPDPE published in 1994 9 has been assumed as starting point in a recent computational study based on MD simulations, 10 from which a series of putative bioactive conformations has been provided: gem-dimethyl groups of the D-penicillamine residues are responsible for the rigidified structure and their adverse steric interactions for the low μ-opioid (MOP) receptor affinity.…”

“…The X-ray crystal structure of DPDPE published in 1994 has been assumed as starting point in a recent computational study based on MD simulations, from which a series of putative bioactive conformations has been provided: gem -dimethyl groups of the d -penicillamine residues are responsible for the rigidified structure and their adverse steric interactions for the low μ-opioid (MOP) receptor affinity. Disulfide bond is prone to reduction following ring opening, so incorporation of different types of linkers could provide conformational diversity involving different cyclization strategies and global and local constrictions; the replacement of disulfide bond with more stable bridges can increase metabolic stability and change the overall conformation in order to improve the receptor binding affinity of the novel compounds. , A systematic and synergistic multidisciplinary approach has been used, over the last decades, for the design of novel peptide ligands with unique biological activity profiles . In this article we propose the design, synthesis, and biological evaluation of new cyclic DPDPE analogues 7a – c containing o -, m -, p -xylene regioisomers, respectively, as μ/δ mixed opioid receptor agonists, using in vitro and in vivo models to examine the antinociception activity of the new entities.…”

Evaluation of the analgesic effect of 4-anilidopiperidine scaffold containing ureas and carbamates

“…The pharmacological profile of such compounds should join high efficacy in chronic pain states reducing the development of tolerance. Significant advantages over a multidrug approach could be: (i) oral administration, (ii) better pharmacokinetic properties, (iii) no drug-drug interactions and (iv) improved compartment targeting 17 . The data obtained so far, indicate that our products have weak affinity for m-opioid receptors, and are not strong inhibitors of FAAH/MAGL.…”

χ-Space Screening of Dermorphin-Based Tetrapeptides through Use of Constrained Arylazepinone and Quinolinone Scaffolds

“…In the search for nonaddictive analgesics with a prolonged duration of action and reduced side effects, a plethora of structural analogues of endo- and exogenous opioid peptides has been explored. − Many peptidomimetic techniques have been applied in this field, including peptoids, retro-inverso analogues, amide bond isosteres, and macrocyclizations …”

“…Receptor selectivity is dependent on the conformational space available to the peptide, and the relative orientation of the Tyr and Phe side chains is indisputably an important feature of opioid peptide pharmacophores. , Since different receptors may require slightly different side-chain orientations for optimal binding events, receptor (sub)­type selectivity can be achieved via introduction of conformationally constrained amino acids. Such conformational constraints provide control over the χ 1 - and χ 2 -space via favoring, disfavoring, or excluding the gauche (−), the gauche (+), or the trans conformation. ,,− In this way, useful information about the preferred and bioactive side chain topology can be obtained. ,, …”