Marc Capet

Congo red protects against toxicity of β-amyloid peptides on rat hippocampal neurones

beta-Amyloid peptides are neurotoxic when applied to primary cultures of hippocampal neurones from the embryonic rat. This neurotoxic effect can be inhibited completely by certain disazo dyestuffs. The most potent of these are Congo Red and Congo Rubin, whilst Direct Garnet and sodium 4-aminonaphthalene-1-sulphonate are inactive. Congo Red also inhibits the neurotoxic effects of the human pancreatic amyloidogenic peptide amylin. It is postulated that these dyes, by interacting with the beta-pleated sheet structure of amyloidogenic peptides, prevent aggregation and hence neurotoxity.

Pharmacological properties of ureido-acetamides, new potent and selective non-peptide CCKB/gastrin receptor antagonists

We present here the pharmacological properties of 3 ureido-acetamide members of a novel family of non-peptide cholecystokinin-B (CCKB) receptor antagonists. RP 69758 (3-(3-[N-(N-methyl N-phenyl-carbamoylmethyl) N-phenyl-carbamoylmethyl] ureido)phenylacetic acid), RP 71483 ((E)-2-[3-(3-hydroxyiminomethyl phenyl) ureido] N-(8-quinolyl) N-[(1,2,3,4-tetrahydro 1-quinolyl)carbonylmethyl]acetamide) and RP 72540 ((RS)-2-[3-(3-[N-(3-methoxy phenyl) N-(N-methyl N-phenyl-carbamoylmethyl) carbamoylmethyl] ureido) phenyl] propionic acid) displayed nanomolar affinity for guinea-pig, rat and mouse CCKB receptors labelled with [3H]pCCK-8 or with the selective CCKB receptor ligand [3H]pBC264. RP 69758 and RP 72540 showed selectivity factors in express of 200 for CCKB versus CCKA receptors. All three compounds had also high affinity for gastrin binding sites in the stomach. The ureido-acetamides behaved as potent antagonists of CCK-8-induced neuronal firing in rat hippocampal slices in vitro, a functional model of brain CCKB receptor mediated responses. RP 69758 is also a potent gastrin receptor antagonist in vivo that dose dependently inhibits gastric acid secretion induced by i.v. injection of pentagastrin in the rat. None of the three ureido-acetamides, at concentrations up to 1 microM, significantly blocked CCK-8-evoked contractions of the guinea-pig ileum in vitro, a CCKA receptor bioassay. In ex vivo binding studies, i.p. administration of RP 69758 and RP 72540 resulted in a dose-dependent inhibition of [3H]pCCK-8 binding in mouse brain homogenate. However, the relative penetration of these ureido-acetamides into the forebrain after peripheral administration was below 0.01%. RP 71483 did not appear to cross the blood-brain barrier in quantities sufficient to prevent [3H]pCCK-8 binding at low doses, a property that makes it suitable for the exploration of the peripheral versus central origin of the behavioural effects observed following systemic administration of CCK. RP 69758, RP 71483 and RP 72540 are highly potent and selective non-peptide CCKB receptor antagonists which are useful tools to explore the physiological functions of CCKB receptors.

From Random Screening of Chemical Libraries to the Optimization of FPP-Competitive Inhibitors of Farnesyltransferase

Together with gene alterations of the p53 tumor suppressor gene, mutations of the ras genes represent the most frequent gene modification umancancers. Ras mutations are found in at least 90% of pancreas, 50% of colon, and 30% of both lung and thyroid cancers (1,2).