Brain-targeted delivery of a leucine-enkephalin analogue by retrometabolic design

Journal of Medicinal Chemistry
K Prokai-TatraiN Bodor

Abstract

A brain-targeted chemical delivery system (CDS) based on retrometabolic drug design was applied to a Leu-enkephalin analogue, Try-D-Ala-Gly-Phe-D-Leu (DADLE). The molecular architecture of the peptide CDS disguises its peptide nature from neuropeptide-degrading enzymes and provides lipophilic, bioreversible functions for the penetration through the blood-brain barrier. These functions were provided by a targetor, a 1,4-dihydrotrigonellyl group, on the N-terminus and a bulky, lipophilic ester group on the C-terminus. A spacer amino acid residue was also inserted between the targetor and the parent peptide to assure the release of DADLE by specific enzymes. Four CDSs were synthesized by segment-coupling method that proved to be superior to sequential elongation in obtaining this type of peptide conjugates. Intravenous injection of the compounds produced a significant and long-lasting response in rats monitored by the tail-flick latency measurements. CDSs having the bulkier cholesteryl group showed a better efficacy than those having the smaller 1-adamantaneethyl ester. The spacer was the most important factor to manipulate the rate of DADLE release and, thus, the pharmacological activity; proline as a spacer produced more potent ...Continue Reading

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Citations

Aug 10, 2000·Medicinal Research Reviews·L ProkaiN Bodor
Aug 7, 2002·European Journal of Pharmacology·Isabelle QuelvenJean-Marie Zajac
Apr 16, 1998·Pharmacology & Therapeutics·N Bodor, P Buchwald
Jun 6, 2000·Advanced Drug Delivery Reviews·N Bodor, P Buchwald
Jul 20, 2002·Bioorganic & Medicinal Chemistry Letters·Katalin Prokai-TatraiLaszlo Prokai
May 11, 1999·Pharmaceutical Science & Technology Today·W M Pardridge
Feb 24, 2006·Organic & Biomolecular Chemistry·Claudine PatteuxVincent Levacher
Mar 28, 1998·SAR and QSAR in Environmental Research·N BodorM J Huang
Apr 6, 2006·The AAPS Journal·Ken A Witt, Thomas P Davis
Jan 1, 2008·The Open Medicinal Chemistry Journal·K Prokai-TatraiL Prokai
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Oct 16, 1999·Journal of Controlled Release : Official Journal of the Controlled Release Society·N Bodor
Feb 14, 2009·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Katalin Prokai-Tatrai, Laszlo Prokai
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