Strategies To Target Kyotorphin Analogues to the Brain
| Autor: | Whei-Mei Wu, Nicholas Bodor, Pei Chen, Laszlo Prokai |
|---|---|
| Rok vydání: | 1998 |
| Předmět: |
Male
Tail Stereochemistry Chemical synthesis Kyotorphin Rats Sprague-Dawley Structure-Activity Relationship chemistry.chemical_compound Drug Delivery Systems Drug Discovery Reaction Time Peptide synthesis Animals Structure–activity relationship Prodrugs chemistry.chemical_classification Analgesics Dipeptide Nicotinamide Tetrapeptide Brain Dipeptides Rats Amino acid chemistry Molecular Medicine Cholesterol Esters Endorphins Oxidation-Reduction |
| Zdroj: | Journal of Medicinal Chemistry. 41:3773-3781 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm970715l |
| Popis: | The design, synthesis, and pharmacological evaluation of brain-targeted chemical delivery systems (CDS) for a kyotorphin analogue (Tyr-Lys) are described. The brain-targeted compound contains the active peptide in a packaged, disguised form, flanked between the lipophilic cholesteryl ester on the C-terminus and the 1, 4-dihydrotrigonellyl redox targetor, attached to the N-terminus through strategically selected L-amino acid(s) spacer. It was found that for successful brain targeting, the epsilon-amine of Lys needs to be also converted to a lipophilic function. Through sequential enzymatic bioactivation, the Tyr-Lys dipeptide is released in a sustained manner, producing significant and prolonged analgesic activity as demonstrated by the rat tail latency test. An alternate strategy was also employed. Lys was replaced by a redox amino acid pair, Nys+ left and right arrow Nys, the nicotinamide left and right arrow 1,4-dihydronicotinamide analogues of Lys (Nys+ is 2-amino-6-(3-carbamoyl-1-pyridiniumyl)hexanoic acid). The Nys form is lipophilic and facilitates delivery in addition to the C- and N-terminal lipophilic functions. Enzymatic oxidation to Nys+ provides the lock-in, followed by removal of the lipophilic groups, releasing Tyr-Nys+ from the brain-targeted analogue (BTRA). Nys+ was shown to be an effective substitution for Arg or Lys. The activities of the CDS and BTRA, respectively, were antagonized by naloxone, supporting the designed brain-targeted processes. The most potent compound is the two-proline spacer containing CDS (CDS-PP), followed by the BTRA. |
| Databáze: | OpenAIRE |
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