Non-Peptide Cholecystokinin-B/Gastrin Receptor Antagonists Based on Bicyclic, Heteroaromatic Skeletons

Abstract

A series of potent and selective cholecystokinin-B/gastrin receptor antagonists based on the dibenzobicyclo[2.2.2]octane (BCO) skeleton which have recently been described were found to show species-dependent behavior when examined in rat and dog models. We now report the discovery of compounds in which the BCO skeleton has been replaced with bicyclic, heteroaromatic frameworks, such as a 5,6-disubstituted indole or benzimidazole. These new ligands maintain the affinity and selectivity profile of the previous compounds in vitro but show a much more consistent behavior pattern in vivo. Representative examples of this class of compound have been shown to inhibit pentagastrin-stimulated acid secretion when administered intravenously at doses of 0.1 mumol kg-1 or less.

RETRACTED: High thermal stable helical coordination polymers

“…as well as the nitrogen atom may result the more interesting architectures. Up to now, the studies of H 3 bidc were mainly focused on the synthesis of therapeutic reagents [11], the coordination compounds based on it are still rarely reported [12], and most of them are isolated compounds [12c-12f]. In this paper, we reported two high thermal stability cobalt(II) coordination polymers [Co(Hbidc)] n (1) and [Co (Hbidc)(H 2 O) 2 ] n (2) by varying the reaction temperature.…”

Evaluation of Three Novel Cholecystokinin‐B/Gastrin Receptor Antagonists: A Study of their Effects on Rat Stomach Enterochromaffin‐Like Cell Activity

“…Selective receptor antagonists will serve as useful tools with which to examine how the ECL cells and other targets respond to gastrin. YF476 (Takinami et al 1997), JB93182 (Hills et al 1996;Kalindjian et al 1996) and AG041R (Bata et al 1996;Kinoshida et al 1996) (fig. 1) are claimed to be potent and selective cholecystokinin-B/gastrin receptor antagonists with binding affinity for CCK-B/gastrin receptors in the nanomolar range.…”

Cholecystokinin antagonists: Pharmacological and therapeutic potential

“…This research resulted in a new series of ortho-disubstituted bicyclic heteroaromatic analogues which maintained the affinity and selectivity demonstrated by the BCO derivatives, but gave a more consistent in vivo profile. 230 Thus, for example, the indole derivative JB93182 (Table XIII, compound 86) was as potent as the BCO analogue 83 in the pentagastrin-stimulated gastric acid secretion model in anaesthetized rats, but exhibited similar potency in chronic gastric fistula dogs. The in vivo species-variable behavior exhibited by the BCO derivatives could be due to the interspecies variation in CCK receptors already commented in the introductory heading 2.…”

“…For example, the adamantly derivative 83, when administered intravenously, was 700-fold less active in chronic gastric fistula dogs hat in Ghosh and Schild anaesthetized rats. 230 This discrepancy prompted further modification to identify a replacement for the BCO framework. This research resulted in a new series of ortho-disubstituted bicyclic heteroaromatic analogues which maintained the affinity and selectivity demonstrated by the BCO derivatives, but gave a more consistent in vivo profile.…”