New CCK2 agonists confirming the heterogeneity of CCK2 receptors: characterisation of BBL454.
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.
Bellier
Bruno
B
Faculté des Sciences Pharmaceutiques et Biologiques, U266 INSERM, FRE 2463CNRS, 4, avenue de l'Observatoire, 75270 Paris Cedex 06, France.
Crété
Dominique
D
Million
Marie-Emmanuelle
ME
Beslot
Françoise
F
Bado
André
A
Garbay
Christiane
C
Daugé
Valérie
V
D000818:Animals; D001552:Benzazepines / Q000008:administration & dosage / Q000494:pharmacology; D002766:Cholecystokinin / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007274:Injections, Intraperitoneal; D008297:Male; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D009842:Oligopeptides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D043887:Receptor, Cholecystokinin B / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000502:physiology*
C490102:(3H)BBL454, peptide; D001552:Benzazepines; D009842:Oligopeptides; D043887:Receptor, Cholecystokinin B; D002766:Cholecystokinin