Abstract
In a brain-targeting prodrug approach for a metabolically stable enkephalin analogue DADLE, specific enzymes are utilized for in vivo prodrug activation. Prolyl oligopeptidase (POP) may be especially useful in this regard. In vitro metabolic stability of the putative metabolites of prodrugs having various “spacers” has shown that POP provides significantly faster release of DADLE from conjugates having dipeptidyl spacer (specifically Xaa-Pro or Xaa-Ala) than alternative peptidases utilized when single amino acids are used as spacers. In vitro half-lives measured in rat brain homogenate showed excellent correlation with CNS-mediated analgesia using the tail-flick model in rats providing, thus, an in vivo substantiation of the prodrug approach relying on POP as the peptidase to release DADLE.
Highlights
Enkephalins are opioids and potential neuropharmaceuticals for pain relief without the undesired side-effects associated with the use of morphine and other alkaloid analgesics [1]
Selected braintargeting chemical delivery system (BTCDS) having Pro-Pro or Ala-Ala spacer and Cho ester on their C-termini (1c and 1d, Fig. 1) were synthesized analogously to that of 1a and 1b (S=Pro and S=Ala, respectively) by a segment coupling method we have developed to obtain these types of peptide conjugates [12]
Stability studies of the predicted biotransformation products, T+-S-DADLE, of the BTCDSs have been performed in rat brain homogenate [17]
Summary
Enkephalins are opioids and potential neuropharmaceuticals for pain relief without the undesired side-effects associated with the use of morphine and other alkaloid analgesics [1]. Alanine (Ala) or proline (Pro)-based spacer (S) was originally chosen because of the suggested involvement of alanyl and prolyl aminodipeptidyl peptidases (EC 3.4.14.2 and/or EC 3.4.14.5) [13] in the enkephalinergic transmission in the brain As it turned out [14], these enzymes can be utilized for the release of other neuropeptides, 2008 Bentham Open. The present studies were undertaken to provide in vitro evidence of this hypothesis [17], together with an in vivo investigation of the pharmacological consequences of introducing Pro-Pro (1c) and Ala-Ala (1d) dipeptidyl spacers into BTCDSs for potential exploitation of POP [16] in braintargeting delivery of DADLE by prodrug design.
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