New drugs that enhance learning and memory are required for the therapy of cognitive diseases, including Alzheimer’s disease and various types of dementia. The incidence of various dementias is rising rapidly as medical and social progresses make the human lifespan longer, placing a great burden on both patients and caregivers. Currently available drugs (acetylcholinesterase inhibitors, NMDA receptor antagonists) that modulate the cholinergic and glutamatergic cognition pathways are essentially palliative in nature and cannot stop neuronal death. Recently, it has been revealed that learning and memory can be enhanced via the GABAergic pathway. This pathway relies on the activation of carbonic anhydrase (CA), responsible for reversible CO2 hydration, and having a critical role in brain homeostasis [1,2]. Specifically, CA has been shown to modulate the GABAergic input of CA1 pyramidal cells via HCO3- production. CA activation was shown to effectively flip the synaptic switch from inhibitory to excitatory, promoting learning [2]. However, further developments toward this alternative approach to modulating learning and memory have been limited by lack of efficient carbonic anhydrase activators with appropriate pharmacological and pharmacokinetic profiles. The talk will present in detail the role of carbonic anhydrases in the brain homeostasis and in cognitive processes, the crystallography-based rational design of CA activators and our synthetic efforts towards the generation of nanomolar-efficient carbonic anhydrase activators [3-5]. Our most recent biological results, in vitro and in vivo on animal models of learning and memory, will be also presented for a complete overview of the CA role in memory and learning. [1] C. T. Supuran, Nat Rev Drug Discov, 2008, 7(2): 168-181. [2] M.-K. Sun, D.L Alkon, Trends Pharm. Sci., 2002, 23 (2), 83-89. [3] K. Dave, M. A. Ilies, A. Scozzafava, C. Temperini, D. Vullo, C. T. Supuran, Bioorg. Med. Chem. Lett., 2011, 21, 2764-2768 (Cover article) [4] K. Dave, A. Scozzafava, D. Vullo, C. T. Supuran and M. A. Ilies Org. Biomol. Chem., 2011, 9, 2790-2800. [5] B. Draghici, , D. Vullo, S. Akocak, E. A. Walker, C. T. Supuran, M. A. Ilies, Chem. Comm., 2014, 50, 5980-5983.

Activation of carbonic anhydrase and its role in enhancing memory and learning

251st National Meeting (2016)

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