Studies on the mechanism of drug-binding to melanin.

The binding to melanin of chlorpromazine, chloroquine, paraquat and Ni²⁺ has been studied in vitro with pigment from beef eyes. The results showed a marked influence of the ionic environment on the ability of the organic substances to bind to melanin, indicating that electrostatic forces between the cationic forms of the substances and anionic sites on the melanin polymer (presumably carboxyl groups) are important for the complex formation. An analysis of the binding by the method of Scatchard showed that more than one binding class must be implicated in the binding of both the organic substances and Nr²⁺ to melanin. Several concordances were found for the data of the paraquat- and Ni²⁺-binding, indicating a dominant influence of electrostatic forces for the melanin-binding of paraquat. However, several indications were found that non-electrostatic contributions must be added to form the binding-sites for chlorpromazine and chloroquine. It is possible that such contributions may be provided by van der Waals forces occurring at the conjunctions of the aromatic rings in the substances and the aromatic indole-nuclei of the melanin. Experiments with chlorpromazine indicated that the positive ion radical of the substance had a very high melanin-affinity. It is suggested that melanin may be able to oxidize chlorpromazine to a positive ion radical, explaining the firm binding of the substance to melanin and the evidence in the literature favouring this possibility are discussed.