In vivo behavioral effects of stable, receptor-selective neurotensin[8-13] analogues that cross the blood-brain barrier

A set of neurotensin[8-13] (NT[8-13]) analogues (KK1-19) has been evaluated in various pre-clinical assays relevant for further development of these compounds as potential antipsychotics. Initial screening of these compounds for induction of hypothermia following systemic (I.V.) injection in rats, an indirect method commonly utilized to measure the central nervous system (CNS) activity of NT[8-13] analogues, identified three peptides, KK1, KK13 and KK14, capable of crossing the blood-brain barrier (BBB). KK1 features 2(S)-azido-7-aminoheptanoic acid (AAHA) in the Arg(8) position and represents the first monosubstituted NT[8-13] analogue that crosses the BBB. KK13 and KK14 both feature AAHA in the Arg(8) position and tert-Leu in the Ile(12) position while KK14 includes a Trp substituted for Tyr(11). When I.P. administered, only the latter two analogues induced a significant hypothermic response. KK13 (1 mg/kg) inhibited amphetamine-induced hyperlocomotion after I.P. injection; this assay is highly predictive for potential antipsychotics. Chronic dosing (5 mg/kg) of this compound over 5 consecutive days failed to induce hypothermic tolerance while the same dose failed to induce measurable catalepsy. KK13 is thus the first NT[8-13] analogue described to date that demonstrates inhibition of amphetamine-induced hyperlocomotion without inducing catalepsy while maintaining day-to-day hypothermic potency.