Metal ion interactions of phenothiazine drugs.

Phenothiazine drugs are versatile antihistamine and anticholinergic compounds. The drugs are based on the phenothiazine heterocycle with an N(10) substituent consisting of a two or three carbon atom chain terminating in a quaternary nitrogen, which is usually present as the hydrochloride salt.When reacted with K[2] MCl[4] (M=Pd,Pt) phenothiazine and non-drug ligands react thus:-K[2]MCl[4] + 2L → ML[2] CL[2] + 2KC1. Far infrared and [13]C n.m.r. spectroscopy confirm that ML[2]Cl[2] is a cis square planar complex, the ligand being bonded to the metal ion through the sulphur atom of the heterocycle.The drug hydrochloride ligands (LH.C1) react differently:- K[2]MCl[4] + LH.Cl → M(LH)Cl[3] + 2KC1. M(LH)C1[3] is also a square planar compound with the ligand sulphur bonded to the MC1[3-] anion. The charge on the anion is balanced by the quaternary exocyclic nitrogen located at the end of the N(10) side chain of the drug.By X-ray crystallography it was found that the N(10) side chain is bent back over the heterocycle in a unique scorpion conformation facilitating the hydrogen bonding interaction between the quaternary nitrogen and the PdCl[3-] anion. This scorpion conformation is quite different from that found in the uncomplexed drug.Using [1]H n.m.r. spectroscopy it has been found that this scorpion conformation is maintained in dmf solution. These results are discussed in the context of the current receptor blocking theory of the action of the drugs, The results obtained appear to be validated for all phenothiazine drugs despite a wide range of 2 and 10 position substituents on these drugs.No reaction was found for phenothiazine and related non-drug ligands with divalent cobalt, nickel and copper chlorides. However these metal ions do react with the drug hydrochlorides thus:- MC1[2] + 2LH.Cl → (LK[+])[2] (MCI[4])[2-]; (M=Co,Ni and Cu). The species (LH[+])[2] (MCI[4])[2-] involves a hydrogen bonded interaction similar to that seen for the Pd and Pt complexes but no sulphur bonding or any coordination of the heterocycle is present for M=Co,Ni or Cu.FeCl[3] oxidises both the drug and non-drug ligands to cation radicals. FeCl[2] , MnCl[2] and ZnCl[2] show no reaction with either the drug or non-drug ligands.3.