Pharmacological Evaluation of Acute and Subacute Toxicity and Antidepressant Effect after Acute Administration of Novel N-substituted Benzamides

The new synthesized N-substituted-benzamides are structurally related to tiapride, sulpiride or amisulpride, drugs mainly used in the treatment of psychosis and depressive states. This dual activity is based on the dose-dependent antagonist properties towards dopamine receptors. At low antidepressant doses, benzamides preferentially block presynaptic dopamine D3 autoreceptors, that control dopamine synthesis and its release into synaptic cleft, whereas at higher antipsychotic doses, the blocking is moved towards postsynaptic dopamine D2 receptors. Our objective was to investigate the acute and subacute toxicity of the new synthesized compounds on mice, followed by the antidepressant activity after intraperitoneally (i.p.) acute administration in non-depressed mice, using the forced swimming test (FST). LD50 after i.p. and per os (p.o.) administration were determined on mice, values being close to those of other benzamides therapeutically used. The histopathological examination showed, for one compound, renal and hepatic toxicity in one of five examined samples. FST evidenced a significant antidepressant effect (p<0.05, „t” Student test), for two of three compounds, when compared with the control group. Rezumat Au fost sintetizaţi noi compuşi benzamidici N-substituiţi, înrudiţi structural cu tiapridul, sulpiridul sau amisulpridul, medicamente folosite atât în tratamentul manifestărilor psihotice, cât şi al stărilor depresive. Această acţiune duală se datorează activităţii antagoniste, dependente de doză, asupra receptorilor dopaminergici. Astfel, la dozele mici antidepresive, benzamidele blochează receptorii presinaptici D3, care modulează sinteza dopaminei şi eliberarea acesteia în fanta sinaptică, în timp ce la dozele mari antipsihotice, blocajul se mută asupra receptorilor dopaminergici D2 postsinaptici. FARMACIA, 2010, Vol. 58, 1