L. Prokai, X. Ouyang, K. Prokai-Tatrai
Nov 1, 1998
Citations
0
Influential Citations
10
Citations
Quality indicators
Journal
European Journal of Medicinal Chemistry
Abstract
Abstract 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, Glu-Leu-Pro-Gly, where the C-terminal glycine (Gly) functions as an amide precursor via peptidyl glycine α-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.