Correlation of activity of chlorpromazine and respective hydroxy, dimethoxy and sulphoxide analogues on dopamine, muscarinic, histamine and calmodulin sites of action.

1. Chlorpromazine (CPZ) is a unique molecule which has many potential sites of action, as well as a propensity to be transformed into a host of metabolites possessing varying degrees of pharmacological and/or toxic reactions. This investigation examined the rank order of potency of CPZ and eight metabolic derivatives with respect to displacement of 3H-spiperone at central dopamine-2 (DA-2) receptors, 3H-pirenzepine at central muscarinic-1 (M-1) receptors, and inhibition of calmodulin-induced activation of cyclic AMP-dependent phosphodiesterase. 2. The most potent CPZ analogues to displace labelled spiperone from DA-2 receptors in rat striatum were: 3-hydroxy-CPZ, CPZ, 3,7-dihydroxy-CPZ, and 7-hydroxy-CPZ. Intermediate potency was observed with 8-hydroxy-CPZ, 3,7,8-trihydroxy-CPZ, and 7,8-dihydroxy-CPZ. Chlorpromazine sulphoxide and 7,8-dimethoxy-CPZ displayed the least activity at DA-2 receptors. 3. Displacement of labelled pirenzepine from M-1 receptors in rat frontal cortex occurred to the greatest extent with CPZ which was one to two orders of magnitude more potent than noted for 3-hydroxy-CPZ greater than 7-hydroxy-CPZ greater than CPZ-sulphoxide greater than 8-hydroxy-CPZ greater than 7,8-dimethoxy-CPZ. The least potent agents were 3,7-and 7,8-dihydroxy-CPZs and 3,7,8-trihydroxy-CPZ. 4. A partially purified calmodulin-sensitive preparation of cyclic AMP-dependent phosphodiesterase from guinea pig heart was most sensitive to inhibition by 7,8-dihydroxy-CPZ, 7,8-dimethoxy-CPZ, 3-hydroxy-CPZ, 7-hydroxy-CPZ, 8-hydroxy-CPZ and CPZ. Least inhibition occurred with 3,7-dihydroxy-CPZ, 3,7,8-trihydroxy-CPZ and CPZ-sulphoxide. 5. The DA-2 receptors were more sensitive to the active CPZ analogues than were the M-1 receptors while calmodulin-activated phosphodiesterase was the least sensitive preparation. 6. Comparisons of data were made with existing information from other laboratories and in general CPZ, 7-hydroxy-CPZ and 3-hydroxy-CPZ were the most potent compounds across different test conditions.