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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Barbiturates / antagonists & inhibitors
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Blood-Brain Barrier
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Central Nervous System / drug effects*
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Central Nervous System Stimulants / chemical synthesis*
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Central Nervous System Stimulants / pharmacokinetics
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Central Nervous System Stimulants / pharmacology*
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Dose-Response Relationship, Drug
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Half-Life
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In Vitro Techniques
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Kinetics
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Lipids / chemistry
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Membranes, Artificial
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Mice
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Prodrugs / chemical synthesis*
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Prodrugs / pharmacokinetics
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Prodrugs / pharmacology*
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Pyrrolidonecarboxylic Acid / analogs & derivatives
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Sleep / drug effects
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Thyrotropin-Releasing Hormone / analogs & derivatives*
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Thyrotropin-Releasing Hormone / chemical synthesis*
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Thyrotropin-Releasing Hormone / pharmacokinetics*
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Thyrotropin-Releasing Hormone / pharmacology*
Substances
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Barbiturates
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Central Nervous System Stimulants
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Lipids
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Membranes, Artificial
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Prodrugs
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Thyrotropin-Releasing Hormone
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pyroglutamyl-glutamyl-proline amide
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Pyrrolidonecarboxylic Acid