title: Prodrugs to enhance central nervous system effects of the TRH-like peptide pGlu-Glu-Pro-NH2.
abstract: Potential prodrugs for the TRH-like tripeptide pGlu-Glu-Pro-NH(2) 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-NH(2) with long-chain primary alcohols emerged as potentially useful prodrugs to improve the central nervous system activity of pGlu-Glu-Pro-NH(2) upon systemic administration, as revealed by the enhancement of analeptic activity in mice.
authors.affiliation: Center for Neurobiology of Aging, College of Medicine, Gainesville, FL 32610-0485, USA.
authors.forename: Katalin
authors.initials: K
authors.lastname: Prokai-Tatrai
authors.forename: Vien
authors.initials: V
authors.lastname: Nguyen
authors.forename: Alevtina D
authors.initials: AD
authors.lastname: Zharikova
authors.forename: April C
authors.initials: AC
authors.lastname: Braddy
authors.forename: Stanley M
authors.initials: SM
authors.lastname: Stevens
authors.forename: Laszlo
authors.initials: L
authors.lastname: Prokai
mesh_terms: D000818:Animals; D001463:Barbiturates / Q000037:antagonists & inhibitors; D001812:Blood-Brain Barrier; D002490:Central Nervous System / Q000187:drug effects*; D000697:Central Nervous System Stimulants / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D066298:In Vitro Techniques; D007700:Kinetics; D008055:Lipids / Q000737:chemistry; D008567:Membranes, Artificial; D051379:Mice; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives; D012890:Sleep / Q000187:drug effects; D013973:Thyrotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: D001463:Barbiturates; D000697:Central Nervous System Stimulants; D008055:Lipids; D008567:Membranes, Artificial; D011355:Prodrugs; D013973:Thyrotropin-Releasing Hormone; C059697:pyroglutamyl-glutamyl-proline amide; D011761:Pyrrolidonecarboxylic Acid