2 research outputs found
Synthesis and preliminary pharmacological evaluation of methoxilated indoles with possible dopaminergic central action
Compounds 5-7 were synthesized from 4-tetralones with o-iodoanilines by a radical nucleophilic substitution or SRN1 reaction, and were pharmacologically evaluated in order to establish their possible antagonistic action on the central dopaminergic receptors. Behavioural parameters, such as stereotypy in rats were measured after intracerebroventricular administration of these compounds at doses of 10 μg/5 μL. Our results demonstrate that compounds 5-7 do not affect stereotypy behaviour. However, they inhibit the apomorphine-induced stereotypy behaviour, suggesting the involvement of the central dopaminergic system. Also we observe that there is a concordance between the behavioural profiles induced by our compounds and those reported for clozapine 8 and ziprasidone 9. It is plausible to suggest that compounds 5-7 could be acting as potential atypical antipsychotic agents. Quantum calculations performed on the basis of a comparative conformational study of their structures indicate a stereoelectronic similarity between the basic nuclei of compounds 4 and 5-7. In addition Molecular Dynamics (MD) simulations performed on compounds 5-7 at the binding site of dopamine D2 receptor suggest that these compounds could interact with the human D2 dopamine receptors.Colegio de Farmacéuticos de la Provincia de Buenos Aire
Synthesis, dopaminergic profile, and molecular dynamics calculations of N-aralkyl substituted 2-aminoindans
Brain dopaminergic system has a crucial role in the etiology of several neuropsychiatric disorders, including Parkinson's disease, depression, and schizophrenia. Several dopaminergic drugs are used to treat these pathologies, but many problems are attributed to these therapies. Within this context, the search for new more efficient dopaminergic agents with less adverse effects represents a vast research field. The aim of the present study was to synthesize N-[2-(4,5-dihydroxyphenyl)-methyl-ethyl]-4,5-dihydroxy-2-aminoindan hydrobromide (3), planned to be a dopamine ligand, and to evaluate its dopaminergic action profile. This compound was assayed as a diastereoisomeric mixture in two experimental models: stereotyped behavior (gnaw) and renal urinary response, after central administration. The pharmacological results showed that compound 3 significantly blocked the apomorphine-induced stereotypy and dopamine-induced diuresis and natriuresis in rats. Thus, compound 3 demonstrated an inhibitory effect on dopaminergic-induced behavior and renal action. N-[2-(-Methyl-ethyl)]-4,5-dihydroxy-2-aminoindan hydrobromide (4) was previously reported as an inotropic agent, and in the present work it was also re-evaluated as a diastereoisomeric mixture for its possible central action on the behavior parameters such as stereotypy and dopamine-induced diuresis and natriuresis in rats. Our results indicate that compound 4 produces an agonistic response, possibly through dopaminergic mechanisms. To better understand the experimental results we performed molecular dynamics simulations of two complexes: compound 3/D2DAR (dopamine receptor) and compound 4/D2DAR. The differential binding mode obtained for these complexes could explain the antagonist and agonist activity obtained for compounds 3 and 4, respectively.Fil: Andujar, Sebastian Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: de Angel, Biagina Migliore. Universidad del Zulia; VenezuelaFil: Charris, Jaime E.. Universidad Central de Venezuela; VenezuelaFil: Israel, Anita. Universidad Central de Venezuela; VenezuelaFil: Suárez Roca, Heberto. Universidad del Zulia; VenezuelaFil: López, Simon E.. Universidad Simon Bolivar; VenezuelaFil: Garrido, Maria R.. Universidad Central de Venezuela; VenezuelaFil: Cabrera, Elvia Victoria. Universidad del Zulia; VenezuelaFil: Visbal, Gonzalo. Instituto Venezolano de Investigaciones Científicas; VenezuelaFil: Rosales, Cecire. Universidad del Zulia; VenezuelaFil: Suvire, Fernando Daniel. Universidad Nacional de San Luis; ArgentinaFil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: Angel Guío, Jorge E.. Universidad del Zulia; Venezuel