Neuroprotective and MAO inhibitory properties of new coumarin derivatives

F Rodríguez-Enríquez1, R González-Franco1, MI Rodríguez-Franco2, L Monjas2, E Quezada3, L Santana3, MJ Matos3, M Yañez1, JA Fontenla1, D Viña1. 1Universidad de Santiago de Compostela, Departamento de Farmacolog í a, Facultad de Farmacia, 15782, Spain, 2Consejo Superior de Investigaciones Cient í ficas, Instituto de Qu í mica M é dica, 28006, Spain, 3Universidad de Santiago de Compostela, Departamento de Qu í mica Org á nica, Facultad de Farmacia, 15782, Spain

Parkinson\'s disease (PD) is a neurodegenerative disorder that is characterized by progressive loss of dopaminergic neurons in the substantia nigra and a decrease of dopamine (DA) in the striatum.

Coumarins, both of natural origin or their synthetic analogues, show many biological activities (antiplatelet, antimicrobial, antiviral and others). Recent studies have found that substituted coumarins including a trans-stilbene group in their structure (coumarin/trans-resveratrol hybrid derivatives), have a promising monoamine oxidase inhibitory activity (MAO-I) .

Drugs that exert neuroprotection against free radicals and/or with capacity to inhibit the MAO activity are adequate to treatment of PD. In this work, we have evaluated the new derivates of coumarin (compounds 1-8) as potential antiparkinsonian drugs:

Initially, we investigated the potential inhibition of MAO-B / MAO-A enzymatic activity following the methodology described by Yáñez et al (1). Most of the coumarin derivatives showed a very effective activity against MAO-B isoform, the isoform that degrades most efficiently the DA. Since one of the greatest difficulties in the therapy of PD is crossing the BBB, a Parallel Artificial Membrane Permeability Assay (PAMPA), was used in order to test the ease of passage, compound 2 being especially promising. Also, it was found that compound 2, as well as compounds 1 and 5, exert neuronal protection in vitro against H2O2.

In order to increase our knowledge about these new compounds, we are evaluating the effects of coumarin derivatives (10 mg/kg, intraperitoneally) on motor activity of normal (n=8) or hypokinetic mice (reserpine, 5 mg/kg administered 24 h prior assays, n=8). The evaluation is made using a computerized animal observation system (EthoVision V. 3.15, Noldus Information Technology, Wageningen, The Netherlands) according to the method previously described (2) with slight modifications. The in vivo assays are in progress.

1. Yáñez M, Fraiz N, Cano E, Orallo F. Biochem. Biophys. Res. Comm. 344, 688-695, (2006).

2. Raviña E, Casariego I, Masague CF, Fontenla JA, Montenegro GY, Rivas ME, Loza MI, Enguix MJ, Villazon M, Cadavid MI, Demontis GC. J. Med. Chem. 43, 4678-4693, (2000).