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.
Faculté des Sciences Pharmaceutiques et Biologiques, U266 INSERM, FRE 2463CNRS, 4, avenue de l'Observatoire, 75270 Paris Cedex 06, France.
Bruno
B
Bellier
Dominique
D
Crété
Marie-Emmanuelle
ME
Million
Françoise
F
Beslot
André
A
Bado
Christiane
C
Garbay
Valérie
V
Daugé
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