Synthesis and Evaluation of a Set of Para-Substituted 4-Phenylpiperidines and 4-Phenylpiperazines as Monoamine Oxidase (MAO) Inhibitors Fredrik Pettersson,* Peder Svensson, Susanna Waters, Nicholas Waters, and Clas Sonesson NeuroSearch Sweden AB, Arvid Wallgrens Backe 20, S-413 46 Gö teborg, Sweden * S Supporting Information ABSTRACT: A series of para-substituted 4-phenylpiperidines/piperazines have been synthesized and their affinity to recombinant rat cerebral cortex monoamine oxidases A (MAO A) and B (MAO B) determined. Para- substituents with low dipole moment increased the affinity to MAO A, whereas groups with high dipole moment yielded compounds with no or weak affinity. In contrast, the properties affecting MAO B affinity were the polarity and bulk of the para- substituent, with large hydrophobic substituents producing compounds with high MAO B affinity. In addition, these compounds were tested in freely moving rats and the effect on the post-mortem neurochemistry was measured. A linear correlation was demonstrated between the affinity for MAO A, but not MAO B, and the levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and 3-methoxytyramine (3-MT) in the striatum. ■ INTRODUCTION Flavin containing monoamine oxidases (MAOs) constitute a heterogeneous family of enzymes that are present in mammals, plants, and microorganisms. In addition to metabolizing foods and pharmaceutical compounds, they are also responsible for the degradation of amine neurotransmitters. There are two distinct types of MAOs, MAO A and MAO B, which share 70% amino acid sequence homology. 1-5 Even though the two isomers have a number of structural similarities and are both bound to the outer mitochondrial membrane, 6 they have different functions in the brain. MAO A catalyzes the oxidative deamination of serotonin (5-hydroxytryptamine, 5-HT), and the therapeutic use of inhibitors of MAO A is primarily in the treatment of depression. 7,8 On the other hand, MAO B is responsible for the degradation of benzylamine and α-phenethylamine, and MAO B inhibitors are used to treat neurodegenerative disorders such as Parkinson’s disease. 9 Dopamine (DA), adrenaline (A), and noradrenaline (NA) are metabolized by both isoforms, albeit more efficiently by MAO A. 10,11 Both MAO A and MAO B are present in the rat brain. 5,12 MAO A is the isoform found primarily within dopaminergic nerve terminals, 13 whereas MAO B is found mainly in striatal neurons and glial cells. 14 Furthermore, it has been shown that MAO A has a predominant effect on dopamine catabolism, leading to production of the metabolite DOPAC (3,4- dihydroxyphenylacetic acid), and that MAO A inhibitors (e.g., clorgyline) therefore reduce striatal DOPAC levels. 6,15 In addition, since more synaptic DA is metabolized by COMT (catechol-O-methyltransferase) to 3-MT (3-methoxytyramine) and less 3-MT is metabolized to HVA (homovanillic acid) by MAO, a concomitant increase in 3-MT levels is observed. Because of the location of MAO B, specific inhibition of this isoform with, for example, selegeline has no effect or only mild effects on DOPAC and 3-MT concentrations. 16 However, in the presence of a MAO A inhibitor, MAO B inhibitors potentiate the effect of MAO A on DOPAC. 17 It is therefore crucial to take into consideration the plasma concentrations of different inhibitors when testing them in vivo, since most MAO inhibitors are only selective up to a certain concentration. MAO inhibitors can bind either reversibly (e.g., moclobemide) or irreversibly (e.g., clorgyline and selegiline) (Figure 1). 18-20 It is believed that the newer reversible agents are less prone to induce tyramine potentiation, a common side effect of MAO inhibitors, than the irreversible inhibitors. 21-23 Most of the known MAO A inhibitors have an aromatic moiety with basic nitrogen at two to four atoms distance from the ring. While the irreversible inhibitors have a functional group that enables covalent binding to the MAO enzyme (e.g., Received: December 15, 2011 Published: March 5, 2012 Figure 1. Examples of MAO A (moclobemide and clorgyline) and MAO B (selegiline and rasagiline) inhibitors. Article pubs.acs.org/jmc © 2012 American Chemical Society 3242 dx.doi.org/10.1021/jm201692d | J. Med. Chem. 2012, 55, 3242-3249