Neurotensin Receptor Antagonists

Abstract

Neurotensin (NT), a peptide hormone widely distributed in the CNS and GI tract of mammals, participates in a wide spectrum of central and peripheral biological functions by interacting with specific membrane bound receptors. Recently, NT receptors related to rat brain and human brain have been cloned and sequenced, and has been shown to belong to the G-protein family of receptors. In addition to its normal biological functions, NT has also been implicated in a variety of CNS and GI related disorders, and suitable antagonists of this hormone would be valuable tools for investigating the roles of NT in the pathophysiology of these diseases. Although considerable efforts have been directed toward synthesis of peptide analogues, this approach failed to provide pure antagonists of NT. Recently, screening of chemical compound libraries and lead optimization techniques, used at various industrial laboratories, have led to the discovery of several potent and structurally diverse nonpeptide antagonists. The medicinal chemistry and biological properties of these nonpeptide NT antagonists are described in this review. In addition, the biological aspects of NT and its receptors, and potential clinical utilities of NT agonists or antagonists are also discussed .