DPDPE potency

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. 

Intestinal inflammation may increase the expression of enteric opioid receptors (see below), and the potency of delta opioid agonists such as DPDPE ([D-Pen2,5]enkephalin) to decrease intestinal transit and mucosal permeability is enhanced in the inflamed mouse gut. The intraperitoneal administration of antisense oligodeoxynucleotides to knock down enteric delta opioid receptor expression is associated with decreases in the inhibitory effects of DPDPE on transit and permeability, particularly in the inflamed intestine [21]. 

A variety of substitutions have been made for Phe in JOM-13 (932-935). Comparison of Phe substitutions in JOM-13 to the same substitutions for Phe" in DPDPE found that modifications that would be expected to affect the conformation of the peptide backbone (e.g., incorporation of NMePhe or D-Phe) had deleterious effects on S-receptor affinity and potency in the MVD in both series (932) the effects of these substitutions were generally greater in the pentapeptide series, however, which may be due to the greater rigidity, and therefore... 

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