Antiulcerogenic and antisecretory effects of a novel diphenylmethane derivative and antiestrogen binding site ligand

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Abstract
N,N-Diethyl-2-[4-(phenylmethyl)-phenoxy]-ethanamine hydrochloride (DPPE) is a para-diphenylmethane derivative that binds selectively and with high affinity to the microsomal antiestrogen binding site (AEBS). Recent studies with DPPE indicate that AEBS is closely related to a lower affinity non-H1, non-H2 histamine site that may be associated with calcium channels; the DPPE-AEBS site is different from that which verapamil binds, however, DPPE, but not verapamil, demonstrates antiproliferative effects in vitro and is antiestrogenic in vivo. We now show that DPPE profoundly inhibits restraint and cold stress and ethanol-induced gastric ulcer formation, accelerates ulcer healing, attenuates the stress-induced rise in plasma corticosterone level, and significantly reduces basal and H2 agonist (dimaprit)-stimulated and, to a lesser extent, bethanechol-stimulated gastric acid output in conscious rats. A nonulcerogenic but prostaglandin-depleting dose of indomethacin completely blocks the inhibitory effects of DPPE on stress ulcer formation. Conversely, verapamil only slightly attenuates dimaprit-stimulated gastric acid secretion and exacerbates ethanol-induced gastric ulcers; its anti-stress ulcer effects are only partially attenuated by indomethacin. These findings support the likelihood that the site of action of DPPE is different from that of verapamil, and that an effect on prostaglandin may, at least in part, contribute to its antiulcer and apparent cytoprotective effects.