Design, synthesis, and evaluation of the antipsychotic potential of orally bioavailable neurotensin (8e13) analogues containing non-natural arginine and lysine residues M. Kyle Hadden a , Kevin S. Orwig a , Kyle P. Kokko a , Jean Mazella b , Thomas A. Dix a,c, * a Department of Pharmaceutical Sciences, Medical University of South Carolina, 280 Calhoun Street, PO Box 250140, Charleston, SC 29425, USA b Institut de Parmacologie Moleculaire and Cellulaire, UMR 6097 Centre National de la Recherche Scientifique, 660 route des Lucioles, 06560 Valbonne, France c Argolyn Bioscience Inc., 2741 Speissegger Drive, Suite 202, North Charleston, SC 29405, USA Received 25 January 2005; received in revised form 14 June 2005; accepted 21 June 2005 Abstract Neurotensin (NT) and its active fragment NT(8e13) elicit behavioral responses typical of clinically used antipsychotic drugs when administered directly to the brain. However, limited peptide stability and oral bioavailability have prevented these compounds from being developed as relevant pharmaceuticals. Recently, our laboratory designed and studied a first-generation NT(8e13) derivative, KK13, that elicited key pharmacokinetic and behavioral responses typical of clinically used antipsychotic drugs when administered to rats parenterally. This compound was the basis for the rational design of a series of second-generation NT(8e13) analogues (KH1eKH30) studied in this paper. Initial screening of these analogues for CNS activity by monitoring hypothermia induction after peripheral administration defined several compounds (KH11, KH24, KH26, and KH28eKH30) that warranted further investigation. Each compound maintained binding affinity for NTR 1 , however, only KH24, KH26, and KH28 (as well as KK13) elicited significant hypothermic responses after oral administration. Of these, KH28 demonstrated an oral activity 3-fold greater than any other analogue; hence it was further characterized in a series of rat behavioral assays. KH28 attenuated D- amphetamine induced hyperlocomotion, a hallmark of current clinically effective antipsychotic drugs, after both IP and oral administration. In addition, tolerance to the compound did not develop after repeated daily dosing, as measured by hypothermic induction as well as attenuation of D-amphetamine induced hyperlocomotion. Finally, KH28 did not produce catalepsy, a deleterious side-effect elicited by classical antipsychotic drugs. KH28 is considered to be an ideal compound for further development as a potential novel antipsychotic. Ó 2005 Elsevier Ltd. All rights reserved. Keywords: Neurotensin; Peptides; Bloodebrain barrier; Arginine; Lysine; Amino acid analogues; Schizophrenia 1. Introduction Several distinct lines of evidence implicate neuro- tensin (NT) in the pathophysiology of schizophrenia and the mechanism of action of antipsychotic drugs (APDs). Anatomically, co-localization of the NT and dopaminergic systems in brain regions associated with * Corresponding author. Department of Pharmaceutical Sciences, Medical University of South Carolina, 280 Calhoun Street, PO Box 250140, Charleston, SC 29425, USA. Tel.: C1 843 876 5092; fax: C1 843 792 1617. E-mail address: dixta@musc.edu (T.A. Dix). 0028-3908/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropharm.2005.06.010 Neuropharmacology 49 (2005) 1149e1159 www.elsevier.com/locate/neuropharm