From cysteamine to MPTP: structure-activity studies with duodenal ulcerogens.
Cysteamine is the first chemical identified that induces acute and chronic duodenal ulcers in rodents. Structure-activity studies with cysteamine, propionitrile and their derivatives, as well as with analogues of toluene, revealed numerous alkyl and aryl duodenal ulcerogens. Among these, one of the most interesting from an etiologic and pathogenetic point of view is the dopaminergic neurotoxin MPTP, which shows structural similarities with toluene. The chemically-induced duodenal ulcers are similar and localized on the anterior and posterior wall of the duodenal bulb. Both cysteamine and MPTP affect endogenous dopamine; MPTP is especially potent in depleting central dopamine and inducing lesions in the substantia nigra. MPTP given in high doses induces Parkinson's disease-like syndrome and gastric ulcers. Cysteamine and propionitrile also cause dyskinesia in large and multiple doses. The motility disorders and duodenal ulcers are abolished by dopamine agonists. Cysteamine and MPTP have been known to increase and decrease gastric acid secretion, respectively. However, both compounds induced duodenal dysmotility, decreased bicarbonate production, and reduced its delivery from distal to proximal duodenum. These factors decrease acid neutralization in the duodenal bulb and contribute to duodenal ulceration. Thus, studies with animal models may reveal endogenous mediators and specific receptors which might be involved in the pathogenesis of duodenal ulceration. Specific structure-activity studies in toxicology may lead to new insights in the pathogenesis and pharmacology of a poorly understood human disorder such as duodenal ulceration.