CORRELATION OF ACTIVITY OF CHLORPROMAZINE AND RESPECTIVE HYDROXY, DIMETHOXY AND SULFOXIDE ANALOGS ON DOPAMINE, MUSCARINIC, HISTAMINE AND CALMODULIN SITES OF ACTION
CORRELATION OF ACTIVITY OF CHLORPROMAZINE AND RESPECTIVE HYDROXY, DIMETHOXY AND SULFOXIDE ANALOGS ON DOPAMINE, MUSCARINIC, HISTAMINE AND CALMODULIN SITES OF ACTION
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DOI：
10.3109/00498258809041664
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发表时间：
1988-03-01
期刊：
影响因子：
1.8
通讯作者：
MANIAN, AA
中科院分区：
文献类型：
--
作者：
PALMER, GC;BLOSSER, JC;MANIAN, AA
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>7-hydroxy-CPZ>CPZ-sulphoxide>8-hydroxy-CPZ>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.
