PHOTOPHYSICS AND SKIN PHOTOTOXICITY OF NEUROLEPTIC DRUGS

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Anti-psychotic or neuroleptic drugs are used primarily for the treatment of schizophrenia, but also have applications in mania, anxiety, dementia and drug abuse. The major used neuroleptics belong to the general tricyclic anti-depressants family (phenothiazines, dibenzazepines and dibenzodiazepines). Most of the derivatives of these drugs do also produces serious side effects, including extrapyramidal syndrome (EPS), tardative dyskinesia, parkinsonism, allergy and photosensitization. Small changes in the structure of the derivatives, change the model of action of the drugs, the potency and the spectrum and severity of the side effects. The molecular photochemical mechanisms for their photosensitizing ability are still unknown, even though they are actually used in the United States to treat thousands and thousands of psychiatric annually. Recent studies on the laser flash photolysis of some phenothiazine derivatives showed that the triplet state of chlorinated phenothiazine derives can be efficiently quenched by the protons in the solution. The effectiveness of the quenching is very sensitive to the structure of the drug and seems to correlate with the phototoxicity. The goal of this project is to measure the photophysical properties of a selected group of tricyclic neuroleptics and to study their short-lived transients, especially the cation radical and the triplet. Basic UV-VIs and luminescence techniques will be employed to study their absorption/emission properties. The transients will be characterized using optical absorption measurements with a Nd-YAG laser set up. For the triplet state of these compounds, the extinction coefficient and the quantum yield will be determined using a comparative method and the triplet-triplet energy transfer principle, respectively. Combined MM+/PM3/RHF theoretical calculations will be performed with HyperCHEM/TM on the whole set of photophysical parameters. The experimental and theoretical values will be correlated with the phototoxicity of the drugs to find out if the triplet transient is directly involved in the phototoxic activity of this drug family. The major goal of this project is to find a molecular/photophysical descriptor for the phototoxic side effect of tricyclic antipsychotics.