A novel α-hydroxyamide, N-propyl-2,2-diphenyl-2-hydroxyacetamide, with anticonvulsant, antidepressant and anxiolytic action

VALENTINA PASTORE; JOSEFINA HIGGS; CRISTINA WASOWSKI; ANDREA ENRIQUE; LUISE.BRUNO-BLANCH; MARIEL MARDER

Mar del Plata

Congreso; XXX Congreso Anual de la Sociedad Argentina de Investigación en Neurociencias; 2015

Epilepsy is a common group of neurological disorderswhose hallmark is unprovoked seizures that can be distressing, harmful andfatal. In patients with epilepsy, anxiety and depression are the most frequentpsychiatric comorbidities but they often remain unrecognized and untreated. Science has focus its efforts to find drugs that canbe active as anticonvulsant/antidepressant/anxiolytic minimizing their sideeffects. Our group has expertise in the synthesis of new molecular entitieswith anticonvulsant, antidepressant and anxiolytic profiles. We found thatmicrowave radiation has simplified and improved the synthesis ofα-hydroxyamides, with good yields, shortened reaction times and carried outwithout solvents or catalysts. All α-hydroxyamides synthetized showedanticonvulsant activities and were not neurotoxic. From these, N-propyl-2,2-diphenyl-2-hydroxyacetamide showedthe most remarkable antidepressant effect in the forced swimming and tailsuspention tests (0.3-30 mg/kg, i.p.), and anxiolytic action in the plus mazetest (3-10 mg/kg, i.p.) in mice. Studies of its mechanism of action, by meansof its capacity to act via the GABAA receptor ([3H]flunitrazepambinding assay), the serotonin 5-HT1A receptor ([3H]8-OH-DPAT binding assay) and the Na+ channel (NaCh) (usingveratrine, a voltage-NaCh agonist in vivo)demonstrated that its effects are not likely related to 5-HT1A orGABAergic pathways and its antidepressant-like effects could be due to its NaChblocking properties.