A newly synthesized pyridine derivative, (Z)-5-methyl-2-[2-(1-naphthyl)ethenyl]-4-piperidinopyridine hydrochloride (AU-1421), as a reversible gastric proton pump inhibitor.

ABSTRACT

A newly synthesized pyridine derivative, (Z)-5-methyl-2-[2-(1-naphthyl)ethenyl]-4-piperidinopyridine hydrochloride (AU-1421), was found to inhibit the gastric proton pump in vitro and in vivo. In the leaky membrane vesicles of hog gastric mucosa, AU-1421 inhibited the K(+)-stimulated H, K-ATPase activity competitively with respect to K+, with a Ki value of 0.18 microM at pH 7.4 and 0.10 microM at pH 6.4. This inhibition was not affected by the length of the preincubation time of the enzyme with AU-1421, and activity was restored by dialysis. In the intact hog gastric membrane vesicles, which developed a pH gradient in the presence of valinomycin, AU-1421 also inhibited the gastric proton pump activity as measured by the quench of acridine orange fluorescence. In the isolated rabbit gastric glands, AU-1421 inhibited the histamine-, dibutyryl cAMP- and K(+)-stimulated uptake of [14C]aminopyrine into gastric glands with similar IC50 values of about 1 microM. Furthermore, AU-1421 suppressed gastric acid secretion in acute fistula rats and Heidenhain-pouch dogs with the same potency as cimetidine. These results suggest that AU-1421 is an antisecretory agent which reversibly inhibits the H,K-ATPase.