SYNTHESIS AND BEHAVIORAL-EVALUATION OF A CHEMICAL BRAIN-TARGETING SYSTEM FOR A THYROTROPIN-RELEASING-HORMONE ANALOG

A chemical brain-targeting system, in which a redox 1,4-dihydropyridin e <=> pyridinium function serves as a targeting moiety and a cholester yl ester contributes to the improved penetration across the blood-brai n barrier, was synthesized for a centrally active TRH analogue, pGlu-L eu-Pro-NH2. Our retrometabolic design was also based on the progenitor sequence, Gln-Leu-Pro-Gly, where the C-terminal glycine (Gly) functio ns as an amide precursor via peptidyl glycine alpha-amidating monooxyg enase (PAM) and glutamine (Gln) is the precursor of the N-terminal pyr oglutamyl (pGlu) by glutaminyl cyclase. The molecular design included an endopeptidase (post-proline cleaving enzyme) cleavable spacer funct ion. Treatment with the chemical targeting system significantly improv ed memory-related behavior, without altering thyroid function, in a pa ssive avoidance paradigm in rats bearing bilateral fimbrial lesions. ( C) Elsevier, Paris.