Abstract
Carbonic anhydrases (CAs, EC 4.2.1.1) activators were shown to be involved in memory enhancement and learning in animal models of cognition. Here we investigated the CA activating effects of a large series of histamine based compounds, including histamine receptors (H1R – H4R) agonists, antagonists and other derivatives of this autacoid. CA activators may be thus useful for improving cognition as well as in diverse therapeutic areas (phobias, obsessive-compulsive disorder, generalised anxiety, post-traumatic stress disorders), for which activation of this enzyme was recently shown to be involved.
Highlights
CO2 is generated in most metabolic processes, being one of the simplest molecules involved in crucial physiologic processes in all life kingdoms[1,2]
Considering the relatively large number of histamine receptors (H1R-H4R) as well as the huge number of agonists/antagonists developed for the management of various disorders, among which allergies, gastritis and gastric ulcers, narcolepsy, acute unilateral vestibulopathy, and atopic dermatitis[33,34], there is a large number of compounds incorporating fragments of the histamine chemotype as well as a wealth of structural modifications which mimic this autacoid
The following structure-activity relationship (SAR) can be worked out from the data reported in Table 1 for activation of the four isoforms hCA I, II, IV and VII: i
Summary
CO2 is generated in most metabolic processes, being one of the simplest molecules involved in crucial physiologic processes in all life kingdoms[1,2]. The carbonic anhydrases (CAs, EC 4.2.1.1) are metalloenzymes which catalyse its interconversion to bicarbonate (Equation (1)[3,4,5,6], generating a proton, and a pH disequilibrium, which is used in most biological systems as a readily available buffering system. The reaction occurs without a catalyst, but at physiological pH values it is exceedingly slow for meeting metabolic needs, as CO2 is a poorly water-soluble gas, which can damage cellular components (e.g. membranes, mitochondria, etc.)[6,7]. Its conversion to water-soluble ions (bicarbonate and protons) counteracts this effect, and interfering with the pH balance, is used to control homeostasis and metabolism, making. In humans 15 CAs are expressed, 12 of which are catalytically active: the cytosolic CA I-III, VII and XIII, the membrane-bound CA IV, the mitochondrial CA VA and VB, the secreted (in saliva and tears) CA
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