Cyclic prodrugs of a model opioid peptide for brain delivery

Prodrug strategies have been employed extensively in recent years in attempts to improve the blood-brain barrier (BBB) permeation characteristics of opioid peptides. For such a prodrug strategy to be successful, the prodrug should have: (i) good solubility and stability; (ii) high permeation across the BBB; and (iii) selective bioconversion in the brain. In the studies described in this dissertation, experiments were designed to determine whether various cyclic prodrugs of the opioid peptide DADLE (H-Tyr-D-Ala-Gly-Phe-D-Leu-OH) prepared by our laboratory met these criteria. These cyclic prodrugs employed either an acyloxyalkoxy linker, coumarinic acid linker, or oxymethyl-modified coumarinic acid linker to connect the N-terminal end to the C-terminal end of DADLE.; Sensitive and selective LC/MS/MS analytical methods for the determination of DADLE and its cyclic prodrugs in biological fluids and tissues were developed. From in vitro stability studies, we showed that the cyclic prodrugs are substrates for esterases in various biological media (plasma, brain and liver homogenate). The prodrugs also exhibited increased metabolic stability to exo- and endopeptidases. In pharmacokinetic studies, esterase-catalyzed bioconversion of the prodrugs to DADLE was observed. The cyclic prodrugs showed favorable physiochemical properties and displayed improved stability compared to DADLE in vivo, even though they were rapidly cleared by the liver. Finally, the permeation characteristics of DADLE and its cyclic prodrugs through the BBB were determined using isolated rat brain perfusion. The favorable physicochemical properties provided the prodrugs good “intrinsic” permeabilities across the BBB. However, the prodrugs exhibited an inability to deliver significant amounts of DADLE to the brain because of their rapid liver clearance, poor “apparent” BBB permeation due to their substrate activity for efflux transporters (e.g., P-gp) and slow bioconversion in the brain.; In conclusion, the cyclic prodrugs of DADLE for targeted brain delivery satisfy some of the criteria for a successful prodrug. Further refinement of the structural features of these chemical linkers is needed to overcome some of the biopharmaceutical/pharmacokinetic problems identified.