STRATEGIES TO TARGET KYOTORPHIN ANALOGS TO THE BRAIN

The design, synthesis, and pharmacological evaluation of brain-targete d 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 cholest eryl ester on the C-terminus and the 1,4-dihydrotrigonellyl redox targ etor, attached to the N-terminus through strategically selected L-amin o acid(s) spacer. It was found that for successful brain targeting, th e epsilon-amine of Lys needs to be also converted to a Lipophilic func tion. Through sequential enzymatic bioactivation, the Tyr-Lys dipeptid e is released in a sustained manner, producing significant and prolong ed analgesic activity as demonstrated by the rat tail latency test. An alternate strategy was also employed. Lys was replaced by a redox ami no acid pair, Nys(+) <-> Nys, the nicotinamide <-> 1,4-dihydronicotina mide analogues of Lys (Nys(+) is 2-amino-6-(3-carbamoyl-1-pyridiniumyl )hexanoic acid). The Nys form is lipophilic and facilitates delivery i n addition to the C- and N-terminal lipophilic functions, Enzymatic ox idation to Nys(+) provides the lock-in, followed by removal;of the lip ophilic groups, releasing Tyr-Nys(+) from the brain-targeted analogue (BTRA). Nys(+) was shown to be an effective substitution for Arg or Ly s. The activities of the CDS and BTRA, respectively,were antagonized b y naloxone, supporting the designed brain-targeted processes. The mst potent compound is the two-proline spacer containing CDS (CDS-PP), fol lowed by the BTRA.