| Based on the "Molecular Packaging" and "Sequential Metabolism" concepts, the peptide segment, Gln-Leu-Pro-Gly, the precursor of (Leu{dollar}sp2rbrack{dollar} TRH, was packaged into a chemical delivery system (CDS), to achieve brain delivery of this important TRH analog ((Leu{dollar}sp2{dollar}) TRH) for the treatment of Alzheimer's disease. The chemical delivery system disguises its peptide nature and provides biolabile, lipophilic functions to penetrate the blood-brain-barrier by passive transport. Through sequential enzymatic metabolism, the final target peptide, PyroGlu-Leu-ProNH{dollar}sb2{dollar}, is retained in brain and released in pharmacologically significant amounts in situ.; A series of chemical delivery systems (CDSs) of Leu{dollar}sp2{dollar}-TRH ((8), (12), (23), (24), (25) (34)) have been synthesized by a stepwise procedure in solution starting from a single amino acid, followed by esterification with cholesterol and by coupling of the respective peptide cholesteryl ester directly with preactivated Boc-amino acids using the DCC/HOBt method.; The CNS-delivery of a pharmacologically significant amount of Leu{dollar}sp2{dollar}-TRH is evidenced by the antagonistic effect on barbiturate-induced anesthesia, the measure of the activational effect on cholinergic neurons, in mice. Significant and reduced anesthetic activity was observed using five fully "packaged" Leu{dollar}sp2{dollar}-TRH, (12), (23), (24), (25) (34), as opposed to the unmodified Leu{dollar}sp2{dollar}-TRH.; The pharmacological consequence of modification with a single Pro, Pro-Pro or Pro-Ala as the spacer (S) portion of the CDSs ((23), (24), (34)) has been a greater than 40 percent ((23)), 50 percent ((24)) or even 55 percent ((34)) decrease in barbiturate-induced sleeping time in mice, as compared to the control group or (Leu{dollar}sp2{dollar}) -TRH. Also, significantly reduced barbiturate-induced sleeping times have been observed when the modifications were made using Ala-Ala, Ala-Pro as the spacer (S) functions of CDSs ((12), (25)).; All of the pharmacological data we obtained suggest the successful delivery to and release in the brain of the active TRH analog, Leu{dollar}sp2{dollar}-TRH, from molecularly packaged delivery systems with different spacer (S) functions, among which Pro-Ala and Pro-Pro serve best. |
