Opioid receptors selective protection

Findings continue to accumulate in the field of endogenous opiates, as exemplified by two tetrapeptides isolated from mammalian brain and found to have high affinity and selectivity for p-opioid receptors. These tetrapeptides are endomorphin-1 (Tyr-Pro-Trp-Phe-NH2) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH2). A number of synthetic analogues have been prepared with the view to improve their metabolic stability and, in some cases, to limit their access to peripheral opioid receptors. The three synthetic endomor-phin analogues Tyr-D-Ala-Phe-Phe-NH2 (6.84), Tyr-D-Arg-Phe-Phe-NH2 (6.85), and Tyr-D-Arg-Phe-Ape-NH2 (6.86), to be discussed in the next section, have potent antinociceptive effects in in vivo inflammatory tests but exhibit modest effects in the CNS. However, and despite the presence of a D-amino acid and a protected C-terminus, they remained sensitive to enzymatic hydrolysis [211][212],... 

Much work has been directed toward the preparation of opioid peptide analogues to alleviate the problem of proteolytic inactivation, to define the several receptors, to achieve receptor selectivity and elicit selective activities thereby minimizing side effects, and generally to imderstand the complex mechanisms involved in substance abuse. For that work to be more fully utilized in health care and in alleviating suffering, delivery processes are required to protect the peptide from proteolytic degradation, to access various sites in the body, - and to provide for the desired release profiles. This problem provides an opportunity for elastic transductional protein-based polymers to fill a much-needed role. 

Some selected E-compounds prepared by alkylation are shown in Fig. 42.21. Whereas 6-0-(2-[ E]fluoroethyl)-6-0-desmethyldiprenorphine O Fig. 42.21a), a nonselective (p, k, 5) opioid receptor ligand, was prepared by [ Fjfluoroethylation with [ EjEETos and subsequent 3-O-deprotection (trityl) in about 20% radiochemical yield (Wester et al. 2000), no protection was required to alkylate 3-N-(2 -[ Fjfluoroethyl)spiperone O Fig. 42.21b),... 

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