Prodrugs to enhance central nervous system effects of the TRH-like peptide pGlu-Glu-Pro-NH2

Potential prodrugs for the TRH-like tripeptide pGlu-Glu-Pro-NH2 were synthesized either by esterifying the Glu side-chain of the parent peptide in solution with alcohols in the presence of resin-bound dicyclohexylcarbodiimide or by solid-phase peptide chemistry. Affinities of these ester prodrugs to lipid membranes as predictors of the transport across the blood–brain barrier were compared by immobilized artificial membrane chromatography, and prodrug activation was tested in the brain tissue of experimental animals. Esters of pGlu-Glu-Pro-NH2 with long-chain primary alcohols emerged as potentially useful prodrugs to improve the central nervous system activity of pGlu-Glu-Pro-NH2 upon systemic administration, as revealed by the enhancement of analeptic activity in mice.