New CCK2 agonists confirming the heterogeneity of CCK2 receptors: characterisation of BBL454

Naunyn Schmiedebergs Arch Pharmacol. 2004 Nov;370(5):404-13. doi: 10.1007/s00210-004-0969-7. Epub 2004 Oct 8.

Abstract

Pharmacological studies were undertaken with a new series of cholecystokinin(2) CCK(2) agonists in order to assign to them a CCK(2A) or CCK(2B) pharmacological profile. The open-field test was chosen as the discrimination test of CCK(2B) agonists. The most interesting agonist, BBL454 (0.03-300 microg/kg) induced hyperactivity which was blocked by a CCK(2) antagonist, the D1 antagonist SCH23390, the delta-opioid antagonist naltrindole, but not a CCK(1) antagonist. All compounds active in the open-field test are characterised by a common structural feature, -COCH(2)CO-Trp-NMeNle-Asp-Phe-NH(2), whereas inactive compounds do not possess such a motive. Therefore, this feature can be considered crucial for CCK(2B) activity. BBL454 (0.03-3 microg/kg) improved memory in a two-trial memory test while it was very weakly active on the peripheral CCK(2) receptor, and did not evoke anxiogenic effects in the plus-maze test. The synthesis of BBL454 is simple, its minimal active dose is 30 ng/kg and no "bell-shaped" responses were observed. These results suggest that BBL454 could be considered to be the new CCK(2B) reference agonist.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Benzazepines / administration & dosage
  • Benzazepines / pharmacology
  • Cholecystokinin / analogs & derivatives*
  • Cholecystokinin / pharmacology
  • Dose-Response Relationship, Drug
  • Injections, Intraperitoneal
  • Male
  • Motor Activity / drug effects*
  • Motor Activity / physiology
  • Oligopeptides / administration & dosage
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology*
  • Rats
  • Rats, Wistar
  • Receptor, Cholecystokinin B / agonists*
  • Receptor, Cholecystokinin B / antagonists & inhibitors
  • Receptor, Cholecystokinin B / physiology*

Substances

  • (3H)BBL454, peptide
  • Benzazepines
  • Oligopeptides
  • Receptor, Cholecystokinin B
  • Cholecystokinin