Di- and trihydroxy analogs of chlorpromazine influence the central activity of adenylate cyclase and cyclic AMP phosphodiesterase.
We previously demonstrated that chlorpromazine (CPZ), 7,8 diOH-CPZ and 3,7,8 triOH-CPZ were potent inhibitors of central adenylate cyclase systems. The present studies were thus designed to observe whether further substitutions of dihydroxy groups on the CPZ molecule would influence adenylate cyclase in broken cell preparations of the rat frontal cortex. The inhibition of adenylate cyclase by 7,8 diOH-CPZ was further found to be noncompetitive with respect to ATP concentration. Raising the Ca++ concentration obliterated adenylate cyclase activation by either dopamine or 5'-guanylylimidodiphosphate (Gpp(NH)p) alone or in combination, while inhibition by 7,8 diOH-CPZ was overcome. The enzyme inhibition by 7,8 diOH-CPZ was not influenced, however, by increasing Mg++ concentration. Incubation of rat cortical homogenates with CPZ, 3,7,8 triOH-CPZ or 6,9 diOH-CPZ inhibited stimulation of adenylate cyclase activity while either 3,7- or 3,8 diOH-CPZ resulted in an enhancement of enzyme activity. In further study, using the high speed cortical supernatant, the high Km form of cyclic AMP phosphodiesterase and its activation by the Ca++-dependent, heat stable regulator protein were inhibited by CPZ, 6,9 dioxo-, 7,8 dioxo-, 3,7diOH-, 3,8 diOH-, 6,9 diOH-, 7,9 diOH- and 7,8 diOH-CPZs, but not by 3,7,8 triOH-CZP. The high affinity-low Km form of the enzyme was inhibited to a considerably lesser extent by these analogs. The studies reveal rather diverse and complicated actions of CPZ and its putative metabolites on central enzyme systems.
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism*; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000201:enzymology*; D002746:Chlorpromazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D051381:Rats
D009419:Nerve Tissue Proteins; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D000262:Adenylyl Cyclases; D002746:Chlorpromazine