pyridinium derivatives of histamine are potent activators of cytosolic carbonic anhydrase isoforms i ii and vii a series of positivelycharged derivatives has been prepared by reaction of histamine with substituted pyrylium salts these pyridinium histamine derivatives were investigated as activators of the zinc enzyme carbonic anhydrase ca ec 4211 and more precisely the human isoforms hca i ii and vii activities from the subnanomolar to the micromolar range were detected for these compounds as activators of the three isoforms confirming the validity of current and previous designs the substitution pattern at the pyridinium ring was the main factor influencing activity the three isoforms showing different structural requirements for good activity related with the number of pyridinium substituting groups and their nature among various alkyl phenyl and parasubstituted styryl moieties we were successful in identifying nanomolar potent and selective activators for each isozyme and also activators with a relatively good activity against all isozymes testedvaluable lead compounds for physiology and pathology studies involving these isozymes