Improving the Affinity and Selectivity of a Nonpeptide Series of Cholecystokinin-B/Gastrin Receptor Antagonists Based on the Dibenzobicyclo[2.2.2]octane Skeleton

Abstract

We have recently described a novel series of nonpeptidic cholecystokinin-B (CCKB)/gastrin receptor antagonists based on a dibenzobicyclo[2.2.2]octane skeleton. We wish now to report on compounds arising out of our earlier work which have substantially greater affinity as antagonists for the CCKB/gastrin receptor system and which maintain, or improve on, the already high selectivity with respect to CCKA receptors. Thus, cis-7-[[[(1S)-[[3,5-dicarboxy-phenyl)amino]carbonyl]-2- phenylethyl]amino]carbonyl]-8-[[(1-adamantylmethyl)amino]- carbonyl]-2,3:5,6-dibenzobicyclo[2.2.2]octane expressed a pKi of 8.80 in mouse cortical membranes at CCKB/gastrin receptors. The selectivity for these receptors over CCKA receptors was in the order of 1000-fold.

Diels–Alder cycloadditions by microwave-assisted, continuous flow organic synthesis (MACOS): the role of metal films in the flow tube

“…The Diels-Alder reaction of diene 1 with dienophile 2 is reported to proceed very slowly under batch heating conditions without catalysis (80% yield after 24 h refluxing in toluene). 5 We examined this reaction, and related difficult cycloadditions, in flow using microwave irradiation and the results are shown in Table 1.…”

Gastrin Agonists and Antagonists

“…His most important observation was that removal of the C‐terminal amide, leaving a phenethylamide, gave rise to compounds which had lost their efficacy at gastrin receptors and hence had become antagonists. There then followed a series of elegant studies in which attempts were made to modify synthetically, the predominantly peptidic nature of the resulting antagonists, in the hope of deriving a suitably stable and potent gastrin antagonist (Rodriguez et al 1987).…”

“…After initial optimisation it was found that the affinity for gastrin could be improved by replacing the sidechain aromatic with an adamantane group, suggesting the requirement of the receptor at this point could best be satisfied simply by an appropriate hydrophobic moiety rather than a more specific aromatic group (Kalindjian et al 1994). Progress was made from the adamantane compound (pK i 6.6) to the di‐acid (pK i 8.8) (Kalindjian et al 1995) by the synthesis of some 200 analogues in a systematic SAR study…”

Terrestrial bdelloid rotifers from Erzurum (Eastern part of Turkey)

“…Thus, anthracene (2) and maleic anhydride (3) were ground together and fused for 15 min to give 1. 11,12 Moreover, adduct 1 was achieved through the refluxing of the same reactants in xylene, 13 toluene, 14 benzene, 15 dioxane, 16 or acetic acid 17 as a solvent. The same reaction was activated by cyclopentadienyl ruthenium cations under mild conditions (83 • C).…”