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/D(2)DAR (dopamine receptor) and compound 4/D(2)DAR. The differential binding mode obtained for these complexes could explain the antagonist and agonist activity obtained for compounds 3 and 4, respectively.
Andujar
Sebastian A
SA
Departamento de Química, Universidad Nacional de San Luís, Chacabuco 915-5700, San Luis, Argentina.
de Angel
Biagina Migliore
BM
Charris
Jaime E
JE
Israel
Anita
A
Suárez-Roca
Heberto
H
López
Simon E
SE
Garrido
Maria R
MR
Cabrera
Elvia Victoria
EV
Visbal
Gonzalo
G
Rosales
Cecire
C
Suvire
Fernando D
FD
Enriz
Ricardo D
RD
Angel-Guío
Jorge E
JE
D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D003198:Computer Simulation; D018491:Dopamine Agonists / Q000138:chemical synthesis / Q000737:chemistry*; D018492:Dopamine Antagonists / Q000138:chemical synthesis / Q000737:chemistry*; D007189:Indans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D009038:Motion; D011485:Protein Binding; D051381:Rats; D013239:Stereotyped Behavior / Q000187:drug effects; D013329:Structure-Activity Relationship
D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D007189:Indans; C006545:2-aminoindan; D001058:Apomorphine