INIMEC - CONICET   05467
INSTITUTO DE INVESTIGACION MEDICA MERCEDES Y MARTIN FERREYRA
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
In vivo determination of anxiolytic activity of a novel pyrazoloquinolinone-derivative at the benzodiazepine receptor.”
Autor/es:
LOPEZ RIVILLI MARISA JUANA; BIGNANTE ELENA ANAHI; MOYANO ELIZABETH; MOLINA VICTOR ALEJANDRO; BRIÑON M C
Lugar:
Ouro Preto-MG, Brasil
Reunión:
Congreso; V Brazilian symposium on medicinal chemistry of the Brazilian Chemical Society (SBQ); 2010
Institución organizadora:
Brazilian Chemical Society
Resumen:
Introduction The pharmacological properties of benzodiazepines have made them the most common GABAA receptors modulating drugs in clinical use, consequently benzodiazepine binding site (BBS) is an interesting target for development of novel drugs.1 Several other types of compounds, such as the pyrazoloquinolinones (PQs) are known to bind to the BBS with high affinity, and show a continuous pharmacological activity as agonists, inverse agonist or antagonists.2 Results and Discussion A novel 2-aryl-2H-pyrazolo[4,3-c]quinolin-3-one was synthesized using the optimized methodology previously reported.3 Multistep synthesis was carried out starting from bromoaniline (1) and diethyl ethoxymethylenemalonate (2) via Gould-Jacobs reaction,4 which were cyclized with p-methoxy- phenylhydrazine (5) to obtain the desired PQ (6) (Scheme 1). Scheme 1. Synthesis of PQ 6 The binding affinity of 6, was evaluated for displacement studies of [3H]-Flunitrazepam ([3H]-FNZ) binding in vitro. The results showed that the PQ tested was able to displace the [3H]-FNZ bound to sinaptosomal membrane showing a value of IC50=0.32 nM (Ki = 0.173). In this work we present the results of the in vivo activity in the Elevated Plus Maze (EPM) test. The EPM, consisting of two open arms crossed with two enclosed arms all being elevated from the ground, is widely used for studying anxiolytic drugs and the neurobiological mechanism of anxiety. The rats on the EPM have tendency to avoid the open arms and stay more on the enclosed arms. Anxiolytic drugs increase the number of entries onto and the time spent on the open arms, whereas anxiogenic agents do the opposite.5 The effect of compound 6 on the anxiety-like behavior of Wistar adult male rats (250-300 g) was evaluated in the EPM. Animals were injected and tested thirty minutes later in the EPM. We tested the following doses: 0.25, 0.5, 1 y 3 mg/kg. The administration of 6 produced a robust anxiolytic effect. One way ANOVA demonstrated that the effect was significant with dose of 0.5 and 1 mg/kg. Post hoc LSD Fisher analysis showed an increase in the percentage of time spent on open arms after the treatment with the 6 in the dose of 0.5 and 1 mg/kg (p < 0.05). The results showed that the locomotor activity was not modified by the drug.6 Conclusions Pyrazoloquinolinone 6 was prepared and tested as central benzodiazepine receptor ligands. This compound: ▪       was well absorbed and crossed the blood-brain barrier. ▪       showed high selective affinitty for BBS by  desplacement of [3H]-FNZ (IC50=0.32 nM). ▪       revealed a significant anxiolytic effect with the dose of 0.5 and 1.0 mg/kg. These results suggest a possible role of this drug as an agonist of the BBS. Acknowledgements To CONICET and SECyT for financial support. To Turina A. (PhD) and Perillo M. (PhD) for the binding test.  ___________________ 1 Hadjipavlou-Litina, R.; Garg, R.; Hansch, C. Chem. Rev. 2004, 104, 3571-3793. 2 Fryer, R. I.; Zhang, P.; Ríos, R.; Gu, Zi-Qiang; Basile, A.; Skolnick, P.;  J. Med. Chem. 1993, 36, 1669-1673. 3 López Rivilli, M. J.; Moyano, E. L.; Yranzo, G. I. Tetrahedron Lett. 2010, 51, 478-481. 4 Gould, R.; Jacobs, W. J. Am. Chem. Soc. 1939, 61, 2890-2895. 5 Cruz, A. P. M.; Frei, F. G.; Graeff, F. G.  Pharmacol. Biochem. Behavior 1994, 49, 171-176. 6 López Rivilli, M. J.; Turina, A. del V.; Bignante, E.A.; Molina, V. H.; Perillo M. A.; Moyano, E. L.; Briñon, M. C. work in redaction to J. Med. Chem.