2,5-diketopiperazines are the simplest cyclic peptides found in nature, commonly biosynthesized from amino acids by different organisms, and represent a promising class of biologically active natural products. Their peculiar heterocyclic structure confers high stability against the proteolysis and constitutes a structural requirement for the active intestinal absorption. Furthermore, the diketopiperazine-based motif is considered as a novel brain shuttle for the delivery of drugs with limited ability to cross the blood-brain barrier (BBB) and can be proposed as an ideal candidate for the rational development of new therapeutic agents. Although these cyclic peptides have been known since the beginning of the 20th century, only recently have they attracted substantial interest with respect to the wide spectrum of their biological properties, including antitumor, antiviral, antifungal, antibacterial and antihyperglycemic activities. In addition to these, the most challenging function of the diketopiperazine derivatives is related with their remarkable neuroprotective and nootropic activity. The aim of the present paper is to provide an overview of the two major classes of diketopiperazines, the TRH-related and the unsaturated derivatives both characterized by a significant ability to protect against neurotoxicity in several experimental models. The neuroprotective profile of these compounds suggests that they may have a future utility in the therapy of neuronal degeneration in vivo, potentially through several different mechanisms.
Six new endomorphin analogues, incorporating constrained amino acids in place of native proline have been synthesized. Residues of (S)-azetidine-2-carboxylic acid (Aze), 3,4-didehydro-(S)-proline (Δ 3 Pro), azetidine-3-carboxylic acid (3Aze) and didehydro-alanine (ΔAla) have been used to prepare [Δ 3 Pro 2 ]EM-2 (1), [Aze 2 ]EM-1 (2), [Aze 2 ]EM-2 (3), [3Aze 2 ]EM-1 (4), [3Aze 2 ]EM-2 (5) and [ΔAla 2 ]EM-2 (6). Binding assays and functional bioactivities for μ-and δ-receptors are reported. The highest affinity, bioactivity and selectivity is shown by peptides 2 and 3 containing the Aze residue.Keywords azetidine carboxylic acids; 3,4-didehydro-(S)-proline; didehydro-alanine; endomorphins; μ-receptors The endogenous neuropeptides endomorphin-1 (Tyr-Pro-Trp-Phe-NH 2 ; EM-1) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH 2 ; EM-2), originally isolated from bovine brain 1 and subsequently from the human brain cortex, 2 continue to attract considerable attention in the field of opioid peptides. In comparison with the other endogenous peptide ligands of opioid receptors, endomorphins (EMs) combine potency and efficacy with high affinity and selectivity towards the μ-opioid receptor, 1,3,4 the receptor most involved with acute analgesic effects in the central nervous system. 5 Furthermore, the EMs proteolytic stability, although low on a general scale, is the highest among the known endogenous opioid peptides 6,7 and their activity is accompanied by reduced cardiorespiratory side effects, as compared with the reference alkaloid ligand morphine. 8,9 All of these properties, render EMs the object of continuous investigations and a promising target for the development of new opioid analgesics. However, *Corresponding author: Phone 520-621-6332 ; Fax 520-621-8407., E-mail address: hruby@email.arizona.edu (V. J. Hruby). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. as found in the case of most short linear natural peptides, native EMs lack critical therapeutic characteristics such as bioavailability, duration of action and oral activity. 10 Research efforts are then focused on the design of analogues and peptidomimetics in order to improve EMs properties as potential drugs as well as to better understand the key structural and conformational features on which receptor recognition and binding are based. 11 NIH Public AccessSeveral chemical modifications performed on EMs have been described previously and many of them were focused on the Pro at position 2. [12][13][14][15][16][17][18][19][20] The presence of Pro, the sole proteinogenic amino acid possessing a cyclic structure and a s...
We report the synthesis and the biological evaluation of two new analogues of the potent dimeric opioid peptide biphalin. The performed modification is based on the replacement of two key structural elements of the native biphalin, namely: the hydrazine bridge which joins the two palindromic moieties and the phenylalanine residues at the 4,4′ positions of the backbone. The new analogues 9 and 10 contain 1,2-phenylenediamine and piperazine, respectively, in place of the hydrazidic linker and p-fluoro-L-phenylalanine residues at 4 and 4′ positions. Binding values are: Knormaliμ=0.51nM and Knormaliδ=12.8nM for compound 9, Knormaliμ=0.09nM and Knormaliδ=0.11nM for analogue 10.
The opioid agonists endomorphins (Tyr–Pro–Trp–Phe–NH2; EM1 and Tyr–Pro–Phe–Phe–NH2; EM2) and morphiceptin (Tyr–Pro–Phe–Pro–NH2) exhibit an extremely high selectivity for μ-opioid receptor. Here a series of novel EM2 and morphiceptin analogues containing in place of the proline at position 2 the S and R residues of β-homologues of proline (HPro), of 2-pyrrolidinemethanesulphonic acid (HPrs) and of 3-pyrrolidinesulphonic acid (βPrs) have been synthesized and their binding affinity and functional activity have been investigated. The highest μ-receptor affinity is shown by [(S)βPrs2]EM2 analogue (6e) which represents the first example of a β-sulphonamido analogue in the field of opioid peptides.
New endomorphin-2 (EM-2) analogues incorporating (Z)-α,β-didehydro-phenylalanine (Δ Z Phe) in place of the native phenylalanine in EM-2 are reported. (2) and Tyr-Pro-Δ Z Phe-Δ Z Phe-NH 2 {[Δ Z Phe 3,4 ]EM-2}(3) have been synthesized, their opioid receptor binding affinities and tissue bioassay activities were determined, and their conformational properties were examined. Compound 2 shows high µ opioid receptor selectivity and µ agonist activity comparable to that of the native peptide. The conformation adopted in solution and in the crystal by N-Boc-Tyr-Pro-Δ Z Phe-Phe-NH 2 (8) is reported.
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