Differentiation of Friend erythroleukemia cells induced by benzodiazepines.

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Abstract
Many benzodiazepines, of the type whose receptors are found in peripheral tissue, cause the differentiation of cultured Friend erythroleukemia cells. The maximal level of induction of Hb synthesis is 10-80% of the cells, depending on the compound tested. The induction is concentration- and time-dependent, requiring micromolar amounts of the drugs and .apprx. 5 days of treatment for full expression. The time course is very similar to that observed for a well-studied inducer, dimethyl sulfoxide. The affinities of the agents for the peripheral-type benzodiazepine binding site are not correlated with their capacity to induce differentiation. The biological effect is stereospecific, since the (3S) stereoisomer Ro11-6896 is at least an order of magnitude more potent than its (3R) enantiomer, Ro11-6893. The benzodiazepine effect exhibits definite structure-activity relationships. A 1-methyl group is an absolute requirement, although this is not sufficient in itself. Hydroxyl and methoxyl groups at the 4'' position enhance the biological activity, but 4''-chloro decreases it. Substitutions at the 2'', 6'' and 4 positions also decrease the biological activity, as does the lack of a 2-carbonyl group. The benzodiazepines apparently act in a specific manner to induce the differentiation of Friend erythroleukemia cells.