Synthesis and preliminary pharmacological evaluation of methoxilated indoles with possible dopaminergic central action

Abstract

Compounds 5-7were synthesized from 4-tetralones with o-iodoanilines by a radical nucleophilicsubstitution or SRN1 reaction, and were pharmacologically evaluated in order to establish their possible antago-nistic action on the central dopaminergic receptors. Behavioural parameters, such as stereotypy in rats were mea-sured after intracerebroventricular administration of these compounds at doses of 10 μg/5 μL. Our resultsdemonstrate that compounds 5-7do not affect stereotypy behaviour. However, they inhibit the apomorphine-in-duced stereotypy behaviour, suggesting the involvement of the central dopaminergic system. Also we observethat there is a concordance between the behavioural profiles induced by our compounds and those reported forclozapine 8and ziprasidone 9. It is plausible to suggest that compounds 5-7could be acting as potential atypicalantipsychotic agents. Quantum calculations performed on the basis of a comparative conformational study oftheir structures indicate a stereoelectronic similarity between the basic nuclei of compounds 4and 5-7. In addi-tion Molecular Dynamics (MD) simulations performed on compounds 5-7at the binding site of dopamine D2re-ceptor suggest that these compounds could interact with the human D2dopamine receptors.