Leu5-enkephalin

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. 

Lee J, Kellaway IW (2000) Combined effect of oleic acid and polyethylene glycol 200 on buccal permeation of [D-ala2, D-leu5]enkephalin from a cubic phase of glyceryl monooleate. Int J Pharm 204 137-144... 

The brush border enzymes in the intestine play a major role in peptide hydrolysis. Thus, both aminopeptidase and endopeptidase activities were detected with [Leu5]enkephalin as the substrate [146],... 

Percutaneous absorption is another route of interest for the administration of peptides [158], with metabolism being a complicating factor [159]. Thus, [Leu5]enkephalin and Tyr-Pro-Leu-Gly-NH2 were rapidly degraded on the dermal side after penetration through rat skin preparations [160]. The use of inhibitors confirmed the involvement of serine proteases and metalloenzymes. 

Fig. 6.35. Major peptidases that act on [Leu5]enkephalin and their primary sites of attack...

The pattern and efficiency of hydrolysis of [Leu5]enkephalin, like that of any peptide, depends to a large extent on its compartmentalization. In other words, the qualitative and quantitative aspects of its degradation vary considerably as a function of species, tissue, and concentration profile. Thus, hydrolysis of [Leu5] enkephalin in rat brain is catalyzed mainly by aminopeptidase, ACE, and neprilysin, in rat lungs by aminopeptidase and ACE, and in rat plasma by aminopeptidase, dipeptidyl peptidase III, and ACE [171][172],... 

The 3-(2-hydroxy-4,6-dimethylphenyl)-3-methylbutanoic acid shown in Fig. 8.23, as well as another phenylpropanoic derivative presented below, have been used as pro-moieties to prepare a number of prodrugs of therapeutic peptides [169] [238], Of interest here is that the pro-moiety is linked to the peptide by both amide and ester bonds to form a cyclic, double prodrug, the two-step activation of which is schematized in Fig. 8.24. Briefly, enzymatic hydrolysis of the ester bond unmasks a nucleophile (in this case, a phenol) that carries out an intramolecular attack on the amide bond, resulting in cy-clization of the pro-moiety and elimination of the peptide. [Leu5]enkephalin was one of the therapeutic peptides used to validate the concept, as illustrated in Fig. 8.25 [241],... 

Fig. 8.25. 3-[2-(Acyloxy)-4,6-dimethylphenyl)-3-methylbutanamide as double pro-moiety of [Leu5]enkephalin [241]. The activation mechanism is identical to that shown in Fig. 8.24.

DPDPE—D-Pen2, D-Pen5-enkephalin DSLET—D-Ser2, Leu5-enkephalin, Thr6 DYN—Dynorphin EM—endomorphin ENK— enkephalin j8-FNA—j8-funaltrexamine, NTH—naltrindole 5 -isothiocyanate nor-BNI—Nor-binaltorphimine. 

DALAMID [D-Ala2]Leu-enkephalin DADL(E) [D-Ala2,D-Leu5]enkephalin DSL(E)T [D-Ser Thr enkephalin DTLET [D-Thr2,Leu5,Thr6]enkephalin... 

The synthesis of tetrapeptides and [leu5]enkephalin by the cobalt(III) technique has been described.209... 

Figure 1. Dose-dependent inhibition of ganglioside synthesis in N4TG1 cells by morphine and [d-A la2, D-Leu5] enkephalin under conditions described in text...

Bunnett, N.W., et al. 1988. Isolation of endopeptidase-24.11 (EC 3.4.24.11, enkephalinase ) from the pig stomach. Hydrolysis of substance P, gastrin-releasing peptide 10, [Leu5] enkephalin, and [Met5] enkephalin. Gastroenterology 95 952. 

This hypothesis of delta receptors in the mouse vas deferens was later further substantiated by the observation of the lack of cross-tolerance between a stable enkephalin analog [D-Ala2, D-leu5]enkephalin (DADLE, see below) and sulphentanyl (a mu agonist) in this tissue after chronic administration in vivo [8]. 

STABLE ENKEPHALIN ANALOGUES [D-Ala2, D-Leu5] ENKEPHALIN (DADLE) AND [D-Ala2, N-Me-Phe4, Met(0)5-ol]ENKEPHALIN (FK 33-824) ARE SELECTIVE DELTA AND MU AGONISTS, RESPECTIVELY... 

Robson LE, Kosterlitz HW. Specific protection of the binding sites of D-Ala2-D-Leu5-enkephalin (delta-receptors) and dihydromorphine (mu-receptors). Proc R Soc Lond B Biol Sci 1979 205 425 132. 

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