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

V. PASTORE; J. HIGGS; C. WASOWSKI; A. ENRIQUE; L. BRUNO-BLANCH; M. MARDER

Mar del Plata

Congreso; XXX Reunión Anual de la Sociedad Argentina de Investigación en Neurociencias (SAN); 2015

SAN

Epilepsy is a common group of neurological disorders whose hallmark is unprovoked seizures that can be distressing, harmful and fatal. In patients with epilepsy, anxiety and depression are the most frequent psychiatric comorbidities but they often remain unrecognized and untreated. Science has focus its efforts to find drugs that can be active as anticonvulsant/antidepressant/anxiolytic minimizing their side effects. Our group has expertise in the synthesis of new molecular entities with anticonvulsant, antidepressant and anxiolytic profiles. We found that microwave radiation has simplified and improved the synthesis of alpha-hydroxyamides, with good yields, shortened reaction times and carried out without solvents or catalysts. All alpha-hydroxyamides synthetized showed anticonvulsant activities and were not neurotoxic. From these, N-propyl-2,2-diphenyl-2-hydroxyacetamide showed the most remarkable antidepressant effect in the forced swimming and tail suspention tests (0.3-30 mg/kg, i.p.), and anxiolytic action in the plus maze test (3-10 mg/kg, i.p.) in mice. Studies of its mechanism of action, by means of its capacity to act via the GABAA receptor ([3H]flunitrazepam binding assay), the serotonin 5-HT1A receptor ([3H] 8-OH-DPAT binding assay) and the Na+ channel (NaCh) (using veratrine, a voltage-NaCh agonist in vivo) demonstrated that its effects are not likely related to 5-HT1A or GABAergic pathways and its antidepressant-like effects could be due to its NaCh blocking properties.