Synthesis and behavioral evaluation of a chemical brain-targeting system for a thyrotropin-releasing hormone analogue

A chemical brain-targeting system, in which a redox 1,4-dihydropyridine <=> pyridinium function serves as a targeting moiety and a cholesteryl ester contributes to the improved penetration across the blood-brain barrier, was synthesized for a centrally active TRH analogue, pGlu-Leu-Pro-NH2. Our retrometabolic design was also based on the progenitor sequence, Gln-Leu-Pro-Gly, where the C-terminal glycine (Gly) functions as an amide precursor via peptidyl glycine alpha-amidating monooxygenase (PAM) and glutamine (Gln) is the precursor of the N-terminal pyroglutamyl (pGlu) by glutaminyl cyclase. The molecular design included an endopeptidase (post-proline cleaving enzyme) cleavable spacer function. Treatment with the chemical targeting system significantly improved memory-related behavior, without altering thyroid function, in a passive avoidance paradigm in rats bearing bilateral fimbrial lesions. (C) Elsevier, Paris.