New CCK2 agonists confirming the heterogeneity of CCK2 receptors: characterisation of BBL454
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- Bellier, B., Crété, D., Million, M. et al. Naunyn-Schmiedeberg's Arch Pharmacol (2004) 370: 404. doi:10.1007/s00210-004-0969-7
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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 CCK2 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.