Enkephalins peptidomimetics

The multiple conformational restriction of dermorphin-related tet-rapeptide analogues that was performed represents a rational design of opioid peptidomimetics characterized by a high degree of structural rigid-ification. This is indicated by the fact that the p-selective agonist H-Hat-D-Orn-Aic-Glu-NH2 contains only two freely rotatable bonds, whereas there are 14 freely rotatable bonds in [Leu5]enkephalin. 

Scheme 55 Oxazabicyclic p-Turn Peptidomimetic and the Enkephalin Analogue Containing the Peptido-mimetid174 ...

F ure 3.28. Peptidomimetics that have been designed based on iterative introduction of constraints into parent peptide and hypotheses concerning receptor-bound conformation. Enkephalin mimetic (388), RGD platelet GPIIb/IIIa receptor antagonists (384,385), thyrohberin [TRH (387)], and somatostatin (383,389).For an overview of recent approaches to peptidomimetic design, see the review by Bursavich and Rich (382). 

Peptides and Peptidomimetics from Combinatorial Libraries. Mixture-based combinatorial peptide libraries have been extensively explored by Houghten and coworkers and have led to the identification of a variety of peptides with affinity for opioid receptors (see Ref 946 for a review). Early hexapeptide libraries, deconvoluted by binding to p opioid receptors and either iterative deconvolution (947)or positional scanning (948 see Ref 946 for a description of these deconvolution techniques), identified sequences related to the enkephalins. Other nonacetylated peptide libraries have identified more varied peptides, some that resemble opioid peptides and some that do not. Iterative deconvolution of a hexapeptide library resulted in identification of both Tyr-Pro-Phe-Gly-Phe-XNH, (X = one of 20 natural amino acids), reminiscent of the... 

For their preparation it is necessary, as a first step, to synthesize Boc-protected a-aza-amino acid monomers. Liquid-phase procedures have been optimized for the synthesis of a MeO-PEG-supported Leu-enkephalin azatide (YaGaG FaLa) analogue [90], Unfortunately, this peptidomimetic does not compete with the natural peptide in an ELISA for a specific monoclonal antibody. This was not completely unexpected by the authors because azatide adopts an extended conformation within the critical glycine region, while the bioactive peptide conformation is thought to be a sort of (3-turn. Starting from N-pro-tected a-aza amino acid residues, the generation of combinatorial azatide libraries seems to be feasible. 

The isolation and identification in 1975 of the endogenous opioid pentapeptides, methionine and leucine enkephalin, represents the intellectual groundbreaking in the field of peptidomimetics. The work demonstrated that, despite their highly disparate structures, these linear pentapeptides and the condensed heterocyclic species morphine elicit their biological response, analgesia, by binding to the opiate receptor. However, despite intensive research efforts to understand this relationship, it is fair to say that more than a quarter century later it remains far from clear. ... 

The endogenous peptides methionine and leucine enkephalin (Tyr-Gly-Gly-Phe-Met and Tyr-Gly-Gly-Phe-Leu) are ligands of the opioid receptors. Like the alkaloid morphine, these peptides exhibit significant analgesic effects. As a result, substantial efforts have been applied to develop peptidomimetic analogues of these compounds. 

Kinetically controlled peptide synthesis synthesis ot bioactive peptides in organic solvent (dermorphin, enkephalin) amino acid oligomerization [22] di- and tripeptide synthesis with peptidomimetic leaving group [23-27]... 

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