Pharmacology of histamine H2 receptor antagonists in the human gastric cancer cell line HGT-1. Structure-activity relationship of isocytosine-furan and imidazole derivatives related to cimetidine.

Imidazole and isocytosine-furan derivatives inhibited H2 receptor activity in HGT-1 cells, in accordance with the following relative potencies (IC50 = 2.3 microM cimetidine as reference): SKF 93479 = cimetidine = 100 greater than metiamide = 62 greater than SKF 92408 = 2 greater than SKF 91581 = 0.07). The Schild plot for cimetidine was linear (slope = 0.97) with a pA2 value of 6.72 +/- 0.12 (Ki = 0.18 microM cimetidine), suggesting competitive inhibition. Preincubation of HGT-1 cells for 10 min with H2 antagonists at 2 microM concentration resulted in 90-100% inactivation (SKF 93479 and oxmetidine) and 65% inactivation (ranitidine) which persisted for 30 min, even after a washout period. Accordingly, the kinetics of 2 microM [3H] SKF 93479 binding to HGT-1 cells revealed a half-time for association of 10 min and a dissociation half-time of 120 min. There was a good correlation between the kinetics and relative potencies of cimetidine and SKF 93479 in inhibiting H2 receptor activity in purified plasma membranes (40 nM) as well as in intact HGT-1 cells preincubated for 2 hr with SKF 93479 before histamine addition (45 nM). Chronic treatment of HGT-1 cells for 6 days with 2 microM SKF 93479 specifically blocked H2 receptor activity since cyclic AMP generation induced by other hormones and agents such as VIP, glucagon, GIP and sodium fluoride was unaltered. In contrast, short term and chronic treatment by cimetidine was readily reversible. The isocytosine-furan derivative SKF 93479 differs from the imidazole analogue cimetidine by its apparent irreversible action, due to the slow onset of association from HGT-1 cells. The isocytosine ring in SKF 93479 and oxmetidine seems to play a preponderant role in their apparent long-lasting, irreversible actions.