Pyridoindoles (carbolines) are relatively common indole alkaloids in most diets and in our ecosystem. Besides 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its active metabolite, MPP+, several psychotropic beta-carbolines have been described to exhibit neurotoxic effects on the dopaminergic system. In this work, we have investigated a new class of neurotoxic P-carbolines, the highly halogenated tetrahydro-beta-carbolines. The present compounds are derived from the condensation of endogenous tryptamine with the hypnotic drug chloral hydrate or by exposure to the industrial solvent trichloroethylene (which can be metabolized to chloral). These tetrahydro-beta-carbolines inhibit the mitochondrial respiratory chain, acting as strong inhibitors of Complex I and partial inhibitors of Complex II. They are also neurotoxic to dopaminergic neurons in primary cell culture. (C) 1999 Wiley-Liss, Inc.