Author: Giovanni Curotto ; Giovanna Tedesco ; Emiliangelo Ratti ; Angelo Reggiani ; Franciscus T.M. van Amsterdam ; David G. Trist ; Antonella Ursini ; Daniela Niccolai ; Robert Barnaby ; Stefano Polinelli ; Mauro Corsi ; Daniele Donati ; Carla Marchioro ; Karen Roberts ; Beatrice Oliosi ; Aldo Feriani ; Paolo G. Cassarà ; Gabriella Finizia ; Maria E. Tranquillini

This article deals with the synthesis and the activities of some 1,5-dialkyl-3-arylureido-1,5-benzodiazepin-2,4-diones which were prepared as potential CCK2 antagonists, with the intention to find a possible follow up of our lead compound GV150013, showing an improved pharmacokinetic profile. The phenyl ring at N-5 was replaced with more hydrophilic substituents, like alkyl groups bearing basic functions. In some cases, the resolution of the racemic key intermediates 3-amino-benzodiazepines was also accomplished. Among the compounds synthesized and characterised so far in this class, the 5-morpholinoethyl derivative 54, was selected as potential follow up of GV150013 and submitted for further evaluation.

01 Aug 2007·British Journal of PharmacologyQ2 · MEDICINE

Cholecystokinin CCK₂ receptors mediate the peptide's inhibitory actions on the contractile activity of human distal colon via the nitric oxide pathway

Q2 · MEDICINE

Article

Author: M Chiarugi ; M. Del Tacca ; M Fornai ; C Blandizzi ; F Crema ; F Baschiera ; P Buccianti ; M Tuccori ; N Ghisu ; L Antonioli ; Rocchina Lucia Colucci

Background and purpose:Cholecystokinin is known to exert stimulant actions on intestinal motility via activation of type 1 cholecystokinin receptors (CCK1). However, the role played by cholecystokinin 2 (CCK2) receptors in the regulation of gut motility remains undetermined. This study was designed to examine the influence of CCK2 receptors on the contractile activity of human distal colon.Experimental approach:The effects of compounds acting on CCK2 receptors were assessed in vitro on motor activity of longitudinal smooth muscle, under basal conditions as well as in the presence of KCl‐induced contractions or transmural electrical stimulation.Key results:Cholecystokinin octapeptide sulphate induced concentration‐dependent contractions which were enhanced by GV150013 (CCK2 receptor antagonist; +57% at 0.01 μM). These effects were unaffected by tetrodotoxin. The enhancing actions of GV150013 on contractions evoked by cholecystokinin octapeptide sulphate were unaffected by Nω‐propyl‐L‐arginine (NPA, neuronal nitric oxide synthase inhibitor), while they were prevented by Nω‐nitro‐L‐arginine methylester (L‐NAME, non‐selective nitric oxide synthase inhibitor). In the presence of KCl‐induced contractions, cholecystokinin octapeptide sulphate elicited concentration‐dependent relaxations (‐36%), which were unaffected by NPA, but were counteracted by GV150013 or L‐NAME. The application of electrical stimuli evoked phasic contractions which were enhanced by GV150013 (+41 % at 0.01 μM).Conclusions and implications:CCK2 receptors mediate inhibitory actions of cholecystokinin on motor activity of human distal colon. It is suggested that CCK2 receptors exert their modulating actions through a nitric oxide pathway, independent of the activity of the neuronal nitric oxide synthase isoform.British Journal of Pharmacology (2007) 151, 1246–1253; doi:10.1038/sj.bjp.0707339

01 Feb 2007·European Journal of PharmacologyQ3 · MEDICINE

CCK2 receptors mediate inhibitory effects of cholecystokinin on the motor activity of guinea-pig distal colon

Q3 · MEDICINE

Article

Author: Luca Antonioli ; Giovanni Gori ; Rocchina Colucci ; Narcisa Ghisu ; Marco Tuccori ; Matteo Fornai ; Fabio Baschiera ; Mario Del Tacca ; Corrado Blandizzi

Cholecystokinin and related peptides are involved in the control of intestinal motility and cholecystokinin receptor ligands might represent new pharmacological tools for the treatment of symptoms associated with functional bowel disorders. However, the respective roles played by cholecystokinin receptor subtypes and the mechanisms underlying these regulatory actions remain undetermined. This study was designed to examine the influence of cholecystokinin receptor subtypes on the motor activity of guinea-pig distal colon. The effects of drugs acting on CCK1 and CCK2 receptors were assessed in vitro on the contractile activity of longitudinal smooth muscle, both under basal conditions and in the presence of transmural electrical stimulation or KCl-induced contractions. The application of cholecystokinin octapeptide sulphate (cholecystokinin-8S) to colonic preparations induced concentration-dependent contractions which were prevented by devazepide (CCK1 receptor antagonist), enhanced by GV150013 (CCK2 receptor antagonist) or N(omega)-nitro-L-arginine methylester (L-NAME, nitric oxide synthase inhibitor), and unaffected by tetrodotoxin. The application of gastrin-17 to colonic preparations resulted in relaxant responses which were insensitive to devazepide, and prevented by GV150013, L-NAME or tetrodotoxin. L-NAME, N(omega)-propyl-L-arginine (NPA, neuronal nitric oxide synthase inhibitor) or GV150013 enhanced electrically evoked contractile responses, whereas devazepide did not. When tested in the presence of L-NAME or NPA the enhancing effect of GV150013 on electrically induced contractions no longer occurred. In the presence of KCl-induced pre-contractions, cholecystokinin-8S or gastrin-17 evoked concentration-dependent relaxations, which were unaffected by devazepide and were counteracted by GV150013, L-NAME, NPA or tetrodotoxin. In conclusion, the present results indicate that, at level of distal colon, CCK1 receptors mediate direct contractile effects on smooth muscle, whereas CCK2 receptors on enteric neurons mediate relaxant responses via nitric oxide release.

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