Gastrin Agonists and Antagonists

: This review generally describes work in the area of CCK2 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 CCK1 selective and an agonist still in vivo. We then go on to describe attempts to mimic a putative 310 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.