In vitro binding and CNS effects of novel neurotensin agonists that cross the blood-brain barrier

Animal studies with neurotensin (NT) directly injected into brain suggest t hat it has pharmacological properties similar to those of antipsychotic dru gs. Here, we present radioligand binding data for some novel hexapeptide an alogs of NT(8-13) at the molecularly cloned rat and human neurotensin recep tors (NTR-1), along with behavioral and physiological effects of several of these peptides after intraperitoneal (i.p.) administration in rats. One un ique analog, NT66L, which had high affinity (0.85 nM) for the molecularly c loned rat neurotensin receptor (NTR-1), caused a drop in body temperature a nd antinociception at doses as low as 0.1 mg/kg after i.p. injection. Al 30 min post-injection, the ED50 for NT66L- induced hypothermia (rectal temper ature) and antinociception (hot plate test) was 0.5 and 0.07 mg/kg, respect ively. At a dose of 1 mg/kg i.p., NT66L caused 100% of the maximum possible effect for antinociception for up to 2 h after administration. At this dos e body temperature lowering was greater than -2.5 degrees C from 20 to 120 min after i.p. administration. These results in animals suggest that NT66L has agonist properties at NTR-1 in vivo after extracranial administration a nd provide support for its further study in behavioral tests predictive of neuroleptic activity. (C) 1999 Elsevier Science Ltd. All rights reserved.