Opioid peptides biological activity

Peptide cyclization significantly reduces this flexibility, as shown by model studies with cyclic pseudodipeptides. When incorporated into biologically active cyclic peptides, potencies are generally retained or even enhanced. But flexibility is still a feature since pseudopeptide analogues of the p-receptor-selective opioid parent peptide, Tyr-c[-D-Lys-Gly-Phe-Leu-], were potent but nonselective with respect to activity toward p- and 6-re-ceptorsJ50]... 

Many biologically active secreted peptides are also amidated at their carboxyl terminal, and acetylated at their amino-terminal. The consequences of these modifications are (a) to reduce the susceptibility of these peptides to degradative actions of extracellular aminopeptidases and carboxypeptidases after their secretion and (b) to influence the biological activity of the peptides. Corticotropin-releasing factor, gastrin, cholecystokinin and vasopressin require the C-terminal amide for full activity [54—56]. Acetylation of the N-terminus of a-MSH is necessary for activity, whereas acetylation of /3-endorphin inhibits its opioid activity [57], The enzymes responsible for acetylation have been identified from bovine and rat intermediate lobes [57] and enzymes with a-amidation activity have been reported in preparations of pituitary secretory granules [54,55]. 

The second application of the CFTI approach described here involves calculations of the free energy differences between conformers of the linear form of the opioid pentapeptide DPDPE in aqueous solution [9, 10]. DPDPE (Tyr-D-Pen-Gly-Phe-D-Pen, where D-Pen is the D isomer of /3,/3-dimethylcysteine) and other opioids are an interesting class of biologically active peptides which exhibit a strong correlation between conformation and affinity and selectivity for different receptors. The cyclic form of DPDPE contains a disulfide bond constraint, and is a highly specific S opioid [llj. Our simulations provide information on the cost of pre-organizing the linear peptide from its stable solution structure to a cyclic-like precursor for disulfide bond formation. Such... 

The two /3-turn structures, pc and Pe are the most stable among those considered. This is in accord with the unconstrained nanosecond simulations of linear DPDPE, which converged to these conformers [14]. Because the cyclic form is relatively rigid, it is assumed that the conformation it adopts in solution is the biologically active one, responsible for its high affinity and specificity towards the 5 opioid receptor. The relatively low population of the cyclic-like structure for the linear peptide thus agrees qualitatively with the... 

The second application of the CFTI protocol is the evaluation of the free energy differences between four states of the linear form of the opioid peptide DPDPE in solution. Our primary result is the determination of the free energy differences between the representative stable structures j3c and Pe and the cyclic-like conformer Cyc of linear DPDPE in aqueous solution. These free energy differences, 4.0 kcal/mol between pc and Cyc, and 6.3 kcal/mol between pE and Cyc, reflect the cost of pre-organizing the linear peptide into a conformation conducive for disulfide bond formation. Such a conformational change is a pre-requisite for the chemical reaction of S-S bond formation to proceed. The predicted low population of the cyclic-like structure, which is presumably the biologically active conformer, agrees qualitatively with observed lower potency and different receptor specificity of the linear form relative to the cyclic peptide. 

Chemical Structures and Biological Activities of Non-Peptide Selective Kappa Opioid Ligands... 

The chemical structures and biological activities of hundreds of opioid analgesics derived from the prototype opioid drug morphine are most comprehensively described in two books published in 1986, one entitled Opioid Analgesics, Chemistry and Receptors by Casy and Parfitt [1] and the other entitled Opiates by Lenz et al. [2]. Follow-up articles include those by Casy in 1989, entitled Opioid Receptors and their Ligands Recent Developments [3] which also includes sections on opioid peptides, affinity labelling and opioid receptor subtypes Rees and Hunter in 1990 [4] covering the... 

The spin-spin coupling constants [2-4] of the enkephalins in solution can be interpreted in terms of folded conformations resembling that of morphine in the placement of the residues which appear important for biological activity. X-ray crystallography and theoretical calculations (4-9) have also shown that methionine and leucine enkephalin adopt conformations similar to those concluded from NMR studies. Hence it would appear that opioid peptides can topographically resemble the opiates by assuming preferred, folded, conformations. However, earlier studies from this laboratory (TO) have shown that NMR data can be interpreted in terms of a conformationally flexible structure for methionine enkephalin. 

Liao S, Alfaro-Lopez J, Shenderovich MD et al (1998) De novo design, synthesis, and biological activities of high-affinity and selective non-peptide agonists of the delta-opioid receptor. J Med Chem 41 4767-4776... 

The data obtained on the relative hydrophobicity of opioid peptides 1U) indicate that the relative hydrophobicity of a given peptide may be affected by the ionic composition of the aqueous medium or not affected (at pH 7.4 in the presence of NaCl and phosphate buffer) depending on the structure of the peptide molecule. The biological activity of the peptides determined in several tests was correlated with their relative hydrophobicity at different ionic composition of the aqueous medium, U). 

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