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.

Schleuservermittelter Transport von Wirkstoffen ins Gehirn

“…Dabei war die Konzentration von AZT im Gehirn nicht signifikant erhçht; weil AZT-CDS aber die AZT-Konzentration im Blut absenkt, resultiert daraus ein hçheres Konzentrationsverhältnis zwischen Gehirn und Blut als bei der Gabe von AZT allein. [38] Das CDS-Verfahren wurde auch verwendet, um verschiedene Neuropeptide wie Enkephalin, TRH [39][40][41] Dihydropyridine wurden auch mit Erfolg zur hirnspezifischen Freisetzung verschiedener Verbindungen wie Dopamin, [32] verschiedener Östrogene [42] und 4-Aminobuttersäure (GABA) eingesetzt.…”

Retrometabolism‐Based Drug Design and Targeting

“…More recently, the CDS approach has been extended to achieve successful brain deliveries of a Leuenkephalin analog [549,550], TRH analogs [551][552][553][554][555][556][557], and kyotorphin analogs [34,558]. Neuropeptides, peptides that act on the brain or spinal cord, represent the largest class of transmitter substance and have considerable therapeutic potential [34,604,605].…”

“…As before, the pharmacological activity was assessed by determining the antagonism of barbiturate-induced sleeping time in mice, and the pipecolic acid analog was found to be even somewhat more effective than the previous package. Kyotorphin Analogs Finally, a kyotorphin analog (Tyr-Lys) that has activity similar to kyotorphin itself [639] was also successfully delivered [34,558]. Kyotorphin (Tyr-Arg) is an endogenous neuropeptide that exhibits analgesic action through the release of endogenous enkephalin, and its analgesic activity is approximately four times larger than that of Met-enkephalin [640].…”

“…Several intermediates and building blocks were also studied, but only administration of the whole molecular package produced significant pharmaceutical response confirming that only the designed metabolic sequence as a whole is effective in delivering peptides across the BBB. Brain-Targeted Redox Analogs Kyotorphin analogs also served for the design and evaluation of a novel and conceptually different method that can provide brain-targeted activity for peptides containing amino acids with basic side chains (lysine, arginine) [558].…”

“…Figure 58 compares the structure of the classical brain-targeted CDS (196) with the structure of the braintargeted redox analog (BTRA) (197) used for the present kyotorphin analog. The e-amine function of lysine could be directly replaced by the nicotinamide function using the Zincke procedure to form pyridinium salts [548,558,[645][646][647]. As shown in Fig.…”