Synthesis and biological evaluations of brain-targeted chemical delivery systems of [Nva2]-TRH

Various chemical delivery systems for [Nva2]-TRH were synthesized and their CNS activity was investigated and compared with that of a similar chemical delivery system of [Leu2]-TRH, previously studied. Sequential metabolism of the chemical delivery system delivered to the brain, starting with the conversion of the dihydrotrigonellyl (DHT) to the trigonellyl (T+) moiety, will provide the lock-in to the brain of the T+-chemical delivery system, which will undergo hydrolysis of the cholesteryl ester, formation of the Pr-amide and cleavage of the spacer-T+ part, allowing ultimately the sustained release of the active [Nva2]-TRH. The CNS activity was assessed by measuring the extent of antagonizing barbiturate-induced sleeping time in mice. The fully packaged DHT-Pro-Pro-Gln-Nva-Pro-Gly-OCh produced robust antagonism, reducing sleeping time from 89 min to 48 min, similar to the Leu2-analogue (49 min). However, the partially substituted [Nva2]-TRH analogues showed little or no CNS activity. The results indicate that the fully packaged delivery system is necessary to produce the successful brain targeting of the precursor construct and effective release of the Gln-Nva-ProNH2.