Gastrin Agonists and Antagonists

Abstract

This review generally describes work in the area of CCK 2 or gastrin receptor agonists and antagonists before focussing on highlights of studies in these areas carried out at the James Black Foundation over the last dozen years. Thus, an alanine scan of BOC-tetragastrin coupled with a bioassay in the isolated mouse stomach led to new insights as to the nature of the function of the various residues of the peptide. This in turn produced molecules such as the peptoid, JB 90118 which was an antagonist in all in vitro systems explored but was found to be CCK 1 selective and an agonist still in vivo. We then go on to describe attempts to mimic a putative 3 10 helical conformation for BOC-tetragastrin which had been suggested by fluorescence studies. Structures based on the dibenzobicylo[2.2.2]octane skeleton appeared to fulfil the requirements of the pharmacophore and promising initial results were obtained after the requisite molecules were synthesised. Optimisation of this series led to compounds with affinities in the nanomolar range but which were lacking in consistency when examined in vivo. Further manipulation, this time of the skeleton, led to molecules such as JB 93182 which were of equivalent affinity but with a better profile of action in vivo. It was found during exploration of the SAR of this new series that even relatively small alterations to the structure could give rise to molecules which behaved as agonists. Attempts to improve the oral bioavailability of JB 93182 by reduction of its molecular weight were aided by a molecular modelling approach which ultimately gave rise to another new series, some imidazole derivatives, exemplified by JB 98248.

Linking Non-peptide Ligand Binding Mode to Activity at the Human Cholecystokinin-2 Receptor

“…This view agrees with our data indicating that Trp and Phe of CCK and interacting residues in the CCK2R are involved in CCK2R activation (14,18). However, in our modeled CCK2R⅐CCK complex, CCK did not adopt a 3 10 helix conformation, and the distance between Trp and Phe was twice that observed in water (26). In CCK2R-bound JB93,242, the distance between the centroids of the two aromatic moieties, the indole and the phenyl ring, is of about 9.5 Å.…”

Treatment of gastric carcinoids type 1 with the gastrin receptor antagonist netazepide (YF476) results in regression of tumours and normalisation of serum chromogranin A

“…Many gastrin receptor antagonists of varying affinity and oral bioavailability have been described. 46 One of these antagonists, netazepide, 23 has been shown to be potent, selective and orally-active in healthy subjects. 47 In this study, we have examined the effect of 12 weeks' oral administration of the gastrin receptor antagonist netazepide on type 1 GC.…”

Gastrin, cholecystokinin and gastrointestinal tract functions in mammals

“…A number of antagonist and agonist tools are available and could be used as therapeutic treatments (Black & Kalindjian, 2002). Thus, on one hand, a CCK 1 antagonist might have therapeutic potential for the treatment of pancreatic disorders as prokinetics for the treatment of gastro-oesophageal reflux disease, bowel disorders and gastroparesis.…”