The gastric H+,K+ ATPase--the gastric acid pump--is the molecular target for the class of antisecretory drugs called the proton-pump inhibitors (PPIs). These compounds--omeprazole, lansoprazole, and pantoprazole--contain, as their core structure, 2-pyridyl methylsulfinyl benzimidazole. The H+,K+ ATPase is a heterodimer composed of a 1034-amino acid catalytic alpha peptide and a glycosylated 291-amino acid beta subunit. The alpha subunit probably contains 10 membrane-spanning sequences; the beta, a single transmembrane segment. The PPIs have a pKa of about 4.0; hence they accumulate only in the acidic secretory canaliculus of the stimulated parietal cell. Here they undergo conversion to a cationic sulfenamide, which then reacts with available cysteines on the extracytoplasmic face of the alpha subunit. Omeprazole reacts and forms disulfide bonds with cys813(822) and cys892; lansoprazole, with cys813(822), cys892, and cys321; and pantoprazole, with cys813 and -822. The antisecretory effect of the drugs reflects their short plasma half-life (approximately 60 min), the number of active pumps during that time, and the recovery of pumps following biosynthesis and reversal of inhibition. These drugs also show synergism with either amoxicillin or clari- thromycin in eradicating Helicobacter pylori, an organism shown to be important in duodenal and gastric ulcer disease. Their action is probably due to elevation of pH in the environment of the organism, rather than to any direct action.

A number of substituted imidazo[1,2-a]pyridines and related analogues were selected for biochemical characterization in vitro against both the purified gastric proton pump enzyme, H+/K(+)-ATPase, and the intact gastric gland. The inhibitory activity in these two in vitro models was then examined for correlation with the gastric antisecretory potency determined for these compounds in vivo by using the histamine-stimulated Heidenhain pouch dog. Analysis of the biological data suggested that the inhibitory activity of the analogues determined in two in vitro models is predictive of their in vivo gastric antisecretory activity following intravenous, but not oral, administration. Furthermore, the good correlation observed between the in vitro and in vivo models suggests that these compounds are gastric proton pump inhibitors in vivo. A molecular modeling study of these compounds using the active analogue approach has defined the molecular volume which is shared by the active analogues, as well as the molecular volume which is common to the inactive analogues. Graphical representation of the difference between these molecular volumes can be interpreted in terms of a hypothetical description of the pharmacophore by means of which 3-(cyanomethyl)-2-methyl-8-(phenylmethoxy)imidazo[1,2-a]pyridine, Sch 28080 (1) and its analogues interact with the gastric proton pump enzyme, H+/K(+)-ATPase.

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Glial S-100 protein, soluble protein, and DNA were quantitatively studied in brains of gerbils chronically exposed to ethanol in a nutritionally complete fluid diet. Eight different brain areas were studied. After exposure to ethanol for 3 months followed by a 4-month post-treatment ethanol-free period, increased amounts of S-100 protein per wet weight were found in the frontal cerebral cortex, the sensory-motor cerebral cortex, the posterior cerebellar vermis, and the brainstem. The increase of S-100 in the posterior cerebellar vermis was paralleled by an increase in DNA per wet weight, which was also increased in the anterior cerebellar vermis. However, a decreased content of DNA was observed in the frontal cerebral cortex, despite the increase of S-100 protein, suggesting a cell loss affecting cells other than astroglial in this area. In the cerebellar vermis, elevated concentrations of soluble proteins per wet weight were found, whereas a decreased amount was found in the anterior cerebellar hemispheres. It is suggested that the S-100 protein acts as a marker for astroglial cell volume and that a concomitant increase of S-100 protein and DNA might indicate an increase in the number of astroglial cells. Thus, our results obtained after ethanol exposure and subsequent ethanol abstinence are compatible with changes consisting of astroglial hypertrophy in the cortex areas and brainstem, as well as astroglial hypertrophy and/or proliferation in the posterior cerebellar vermis, a clear sign of the preceding noxae.