Structural requirements of non-peptide neurotensin receptor antagonists

Neurotensin has a wide range of pharmacological effects in peripheral tissues and in the central nervous system. The crystal structures of two potent and selective neurotensin receptor antagonists, SR 48692 (I) and SR 48527 (II) have been determined and are reported in this work. By using computational calculations (semiempirical molecular orbital AM1) we studied the conformational properties of those compounds, including an inactive analogue SR 49711 (III) for comparison. Considering the pharmacological properties related to SR 48692 (I) and to optically synthetic analogues SR 48527 (II) and SR 49711 (III), we propose a model of bioactive conformation adopted by those neurotensin receptor antagonists.