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

Beth M. Tyler, Christopher L. Douglas, Abdul Fauq, Yuan Ping Pang, Jennifer A. Stewart, Bernadette Cusack, Daniel J. McCormick, Elliott Richelson

Research output: Contribution to journalArticle

65 Scopus citations

Abstract

Animal studies with neurotensin (NT) directly injected into brain suggest that it has pharmacological properties similar to those of antipsychotic drugs. Here, we present radioligand binding data for some novel hexapeptide analogs of NT(8-13) at the molecularly cloned rat and human neurotensin receptors (NTR-1), along with behavioral and physiological effects of several of these peptides after intraperitoneal (i.p.) administration in rats. One unique analog, NT66L, which had high affinity (0.85 nM) for the molecularly cloned rat neurotensin receptor (NTR-1), caused a drop in body temperature and antinociception at doses as low as 0.1 mg/kg after i.p. injection. At 30 min post-injection, the ED50 for NT66L-induced hypothermia (rectal temperature) and antinociception (hot plate test) was 0.5 and 0.07 mg/kg, respectively. 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 dose body temperature lowering was greater than -2.5°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 and provide support for its further study in behavioral tests predictive of neuroleptic activity. Copyright (C) 1999 Elsevier Science Ltd.

Original languageEnglish (US)
Pages (from-to)1027-1034
Number of pages8
JournalNeuropharmacology
Volume38
Issue number7
DOIs
StatePublished - Jul 1 1999

Keywords

  • Agonist
  • Antinociception
  • Atypical neuroleptic
  • Blood-brain barrier
  • Hypothermia
  • Neurotensin

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

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