Phenothiazine drugs and metabolites: molecular conformation and dopaminergic, alpha adrenergic and muscarinic cholinergic receptor binding.

The solid state molecular structures of methoxypromazine and N-monodesmethyl chlorpromazine sulphoxide were determined by X-ray crystallography, as an extension of previous studies on the molecular structures of chlorpromazine sulphoxide and methotrimeprazine sulphoxide. The binding affinities of phenothiazine drugs and metabolites with known crystal structures to dopaminergic, alpha adrenergic and muscarinic cholinergic receptors in rat brain were examined using radio-ligand binding techniques. Comparison of their solid state molecular structures and potencies in neurotransmitter receptor binding reveals that these compounds exist in two different conformations: One, associated with low biological activity, has an angle between the planes of the two aryl rings in the range of 155-160 degrees, and a torsion angle of -80 to -84 degrees around the N(10)-C bond of the side-chain, calculated from the substituted benzene ring. In the other conformation, which is found in the biologically active derivatives, the angle between the planes of the two aryl rings is in the range of 134-145 degrees, and the torsion angle around the N(10)-C bond of the side-chain is in the range of 64-69 degrees or 129-144 degrees. The "active" and "inactive" conformations thus have the side-chain on opposite sides of the ring system.