Issue in Honor of Prof. Vincenzo Tortorella ARKIVOC 2004 (v) 32-43
Synthesis and biochemical evaluation of (R)-5-acyloxymethyl- and (S)-5-acylaminomethyl-3-(1H-pyrrol-1-yl)-2-oxazolidinones as new anti-monoamine oxidase (anti-MAO) agents
Antonello Mai,a Marino Artico,*a Sergio Valente,a Ilaria Cerbara,a Olivia Befani,b Paola Turini,b Laura Dalla Vedova,b and Enzo Agostinelli*b
a Dipartimento di Studi Farmaceutici, Università degli Studi di Roma “La Sapienza”, P.le A. Moro 5, 00185 Roma, Italy b Dipartimento di Scienze Biochimiche “A. Rossi Fanelli” and Centro di Biologia Molecolare del CNR, Università degli Studi di Roma “La Sapienza”, P.le A. Moro 5, 00185 Roma, Italy E-mail: MA, marino.artico@uniroma1.it; EA, enzo.agostinelli@uniroma1.it
In honour of Professor Vincenzo Tortorella in the occasion of his “Fuori Ruolo” status (received 06 Oct 03; accepted 26 Nov 03; published on the web 09 Jan 04)
Abstract (R)-5-Acyloxymethyl- and (S)-5-acylaminomethyl-3-(1H-pyrrol-1-yl)-2-oxazolidinones 2a-s were synthesized as pyrrole analogues of toloxatone (Humoryl®), an anti-MAO agent used in clinical therapy because of its antidepressant properties. Their ability to inhibit the enzymatic isoforms MAO-A and MAO-B was evaluated. From the data most 2a-s showed high reversibility and selective MAO-A inhibitory activity. They exhibited an inhibitory potency (KiMAO-A) of 0.16-0.90 µM comparable to that found for toloxatone (KiMAO-A = 0.38 µM), the A isoform being 11-fold more selective. The results indicate that 2a-s show promise as new antidepressant agents.
Keywords: MAO-A, MAO inhibitors (MAOIs), 2-oxazolidinones, 3-(1H-pyrrol-1-yl)-2- oxazolidinones, antidepressant agents
Introduction
Monoamine oxidase (MAO, EC 1.4.3.4) catalyzes the oxidative deamination of biogenic amines both from exogenous and endogenous sources, such in the central nervous system and in peripheral tissues. This enzyme is a flavoprotein tightly bound to the mitochondrial outer membranes of neuronal, glial and other cells.1 On the basis of their different amino acid sequences, substrate and inhibitor specificities two subtypes of MAO, termed MAO-A and MAO-B, have been described. Isoform A preferentially oxidases serotonin, adrenaline and norepinephrine, and is selectively inhibited by clorgyline, whereas isoform B mainly catalyses the oxidative deamination of ß-phenylethylamine and benzylamine, and is selectively inhibited by L-deprenyl.2 Both isoenzymes appear to consist of two subunits3,4 coded by different genes, and they have a 70% amino acid identity.5 Each isoenzyme has an FAD moiety covalently linked to a cysteine residue, Cys404 (MAO-A) and Cys397 (MAO-B), through a
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