RELATIONSHIP BETWEEN STRUCTURE AND PHOTOBIOLOGICAL ACTIVITY OF 7-NITRO-1,4-BENZODIAZEPINES

Authors

  • P. J. G. Cornelissen,

    1. Department of Pharmacochemistry, Subfaculty of Pharmacy, State University of Leyden, Gorlaeus Laboratories, Wassenaarseweg 76, P.O. Box 9502-2300 RA
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    • Boehringer Ingelheim B.V., P.O. Box 60, 2000 AB Haarlem, The Netherlands.

  • G. M. J. Beijersbergen van Henegouwen,

    1. Department of Pharmacochemistry, Subfaculty of Pharmacy, State University of Leyden, Gorlaeus Laboratories, Wassenaarseweg 76, P.O. Box 9502-2300 RA
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  • G. R. Mohn

    1. Department of Radiation Genetics and Chemical Mutagenesis, State University of Leyden, Sylvius Laboratories, Wassenaarseweg 72, P.O. Box 9503–2300 RA Leyden, The Netherlands
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Abstract

Abstract— The photobiological activity of nitrazepam, the active ingredient of the drug Mogadon®. which is known to induce phototoxic effects, that of clonazepam, the active ingredient of the drug Rivotril® and that of flunitrazepam, the active ingredient of the drug Rohypnol®, has been investigated. Using Salmonella typhimurium strain TA-100 as the test organism for cytotoxicity, it was demonstrated that not only nitrazepam, but also the structurally related compounds clonazepam and flunitrazepam were phototoxic. Furthermore, it was shown that this phototoxic effect was due to a photodynamic action of the compounds. Investigations of the (photo)biological activity of the decomposition products (7-nitroso, 7-hydroxylamino, 7-amino analogues and the azoxy dimer) of the parent 7-nitro compounds revealed that they were not involved in the phototoxic effect.

Investigations on structurally related benzodiazepines have established that a 7-nitro substituent in the benzodiazepine nucleus is the structural characteristic responsible for the appearance of phototoxicity and that the magnitude of this phototoxic effect is strongly determined by the presence or absence of a methyl-group at the N-1 position.

Finally, photomutagenicity tests performed with the same bacterial indicator indicated that under the present experimental conditions the oxygen dependent reactive species formed upon irradiation of nitrazepam, clonazepam and flunitrazepam with longwave UV light did not exert mutagenic effects.

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