Enkephalins cyclic derivatives

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],... 

As in the case of cyclic enkephalin analogs, conformationally constrained 6-selective peptides with the sequence Tyr-o-X-Phe were also prepared by cyclization through a disulfide bond. Cyclization between o-Cys in position 2 and D-Pen in position 4 yielded the tetrapep-tide derivative Tyr-cyc/o[D-Cys-Phe-D-Pen]-OH (JOM-13, 249), which contains a fairly... 

Sequential catalytic hydrogenation of the imine bond followed by hydrogenoly-sis of the resultant yV-diphenylmethylamine is an alternative method of deprotection which was used in a solid-phase synthesis of O-glycosyl cyclic Enkephalin analogues [Scheme 8.236]. Note the comprehensive deprotection of 4 benzyl ethers, a diphenylmethyl ester, and an N-diphenylmethyleneamine in a single operation. iV-Diphenylmethyleneamine derivatives of serine have also been applied to the synthesis of Sphingosines. ... 

Macrocyclic modulators of the p-opioid reeeptor inelude cyclic p-casomor-phin- and enkephalin- analogs as well as so ealled atypical cyclic peptides derived from endomorphin-1. 

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