L-708,474: The C5-cyclohexyl analogue of L-365,260, a selective high affinity ligand for the CCKB/gastrin receptor
The synthesis of several C5-cycloalkyl benzodiazepines are described and their affinities for CCK receptors has been determined. The C5-cyclohexyl analogue (L-708,474) is one of the most potent and selective CCKB receptor ligands yet reported.
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2 CCK-B Antagonists in the Control of Anxiety and Gastric Acid Secretion
2000, Progress in Medicinal ChemistryCitation Excerpt :Development of an ex vivo binding assay using [125I]- Bolton Hunter CCK-8S enabled brain penetration to be estimated for the lead tetrazole (8), in mouse, following i.v. administration [56], This showed the compound to be poorly brain penetrant with a brain:plasma ratio of 0.02 (cf. L-365,260, ratio 0.48). Subsequently a significant discovery was made within Merck with the finding that the phenyl group of L-365,260 may be effectively replaced by a cyclohexyl group giving L-708,474 (10) [57]. This change led to enhanced CCK-B receptor affinity and selectivity (Table 2.2).
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