The effect of 2-substitution on conformations and brain concentrations of phenothiazine-neuroleptics in relation to dopamine-antagonism

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Abstract
Conformational energies of promazine, chlorpromazine and triflupromazine were calculated with the INDO-method and plotted as a function of two torsion angles. Distance maps were constructed for the N-S and N-2-substituent distances and compared with the N-O distances in dopamine in its preferred conformation, demonstrating the flexibility of the phenothiazine molecules, and showing that interactions with various dopamine-receptor sites, are likely. To eliminate the influence of transport and distribution on the activity, rat brain concentrations of the phenothiazines were determined simultaneously with the increase in striatal homovanillic acid (HVA) concentrations. Concentrations causing a 300% rise in HVA (taken as a measure of neuroleptic activity) were compared with i.p. doses inducing the same rise in HVA, showing that relative potencies based on brain concentrations and relative potencies obtained from i.p. doses were virtually equal. As the increase in lipophilicity does not significantly improve penetration into the brain, it is concluded that the enhancing effect of 2-substitution on the neuroleptic activity might be due to (a) the increase in the probability of conformations in which the side chain is directed towards one side of the molecule and (b) to a direct interaction with the receptor at a site corresponding with one of the dopamine oxygens.