title: Strategies to target kyotorphin analogues to the brain.
abstract: 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.
authors.affiliation: Center for Drug Discovery, College of Pharmacy, University of Florida, Box 100497 JHMHC, Gainesville, Florida 32610-0497, USA.
authors.forename: P
authors.initials: P
authors.lastname: Chen
authors.forename: N
authors.initials: N
authors.lastname: Bodor
authors.forename: W M
authors.initials: WM
authors.lastname: Wu
authors.forename: L
authors.initials: L
authors.lastname: Prokai
mesh_terms: D000700:Analgesics / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002788:Cholesterol Esters / Q000737:chemistry; D004151:Dipeptides / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016503:Drug Delivery Systems; D004723:Endorphins / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D013329:Structure-Activity Relationship; D013623:Tail
chemical_list: D000700:Analgesics; D002788:Cholesterol Esters; D004151:Dipeptides; D004723:Endorphins; D011355:Prodrugs; C114808:tyrosyl-lysine; C019448:kyotorphin