prodrugs of thyrotropin-releasing hormone and related peptides as central nervous system agents高活性thyrotropin-releasing激素及相关肽作为中枢神经系统代理.pdf

Molecules 2009, 14, 633-654; doi:10.3390/molecule OPEN ACCESS molecules ISSN 1420-3049 /journal/molecules Review Prodrugs of Thyrotropin-Releasing Hormone and Related Peptides as Central Nervous System Agents Katalin Prokai-Tatrai 1,* and Laszlo Prokai 2 1 Department of Pharmacology Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, USA 2 Department of Molecular Biology Immunology, University of North Texas Health Science Center, Fort Worth, TX, USA; E-mail: lprokai@ (L.P.) * Author to whom correspondence should be addressed; E-mail: kprokai@; Tel.: +1-817- 735-0617; Fax: +1-817-735-2118. Received: 1 January 2009; in revised form: 21 January 2009 / Accepted: 5 February 2009 / Published: 6 February 2009 Abstract: Prodrug design for brain delivery of small- and medium-sized neuropeptides was reviewed, focusing on thyrotropin-releasing hormone and structurally related peptides as examples. We have summarized our most important advances in methodology, as well as assessed the benefits and limitations of bioreversible chemical manipulation techniques to achieve targeting of the parent molecules into the central nervous system. The value of prodrug-amenable analogues as potential drug-like central nervous systems agents was highlighted. Keywords: Neuropeptide; CNS-delivery; TRH; Analogue; Prodrug; Prodrug-amenable analogue. 1. Introduction Drugs face a formidable obstacle in reaching the central nervous systems (CNS) due