New CCK2 agonists confirming the heterogeneity of CCK 2 receptors: Characterisation of BBL454

Abstract

Pharmacological studies were undertaken with a new series of cholecystokinin2 CCK2 agonists in order to assign to them a CCK2A or CCK2B pharmacological profile. The open-field test was chosen as the discrimination test of CCK2B agonists. The most interesting agonist, BBL454 (0.03-300 μg/kg) induced hyperactivity which was blocked by a CCK 2 antagonist, the D1 antagonist SCH23390, the δ-opioid antagonist naltrindole, but not a CCK1 antagonist. All compounds active in the open-field test are characterised by a common structural feature, - COCH2CO-Trp-NMeNle-Asp-Phe-NH2, whereas inactive compounds do not possess such a motive. Therefore, this feature can be considered crucial for CCK2B activity. BBL454 (0.03-3 μg/kg) improved memory in a two-trial memory test while it was very weakly active on the peripheral CCK2 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 CCK2B reference agonist. © Springer-Verlag 2004.