Synthesis of 4-methyl-thio-phenyl-propylamine and the evaluation of its interaction with different amine oxidases Alejandra Gallardo-Godoy, Mar Hernandez, Elisenda Sanz and Mercedes Unzeta* Institut de Neurocie `ncies-Departament de Bioquı´mica i Biologia Molecular, Facultat de Medicina, Universitat Auto ´noma de Barcelona, Campus Universitari de Bellaterra, E-08193 Bellaterra, Barcelona, Spain Received 16 April 2003; accepted 1 October 2003 Abstract—A new molecule, the 4-methyl-thio-phenyl-propylamine (PrNH 2 ) was synthesized and its biological interaction with dif- ferent amine oxidases such as semicarbazide sensitive amine oxidase (SSAO) [E.C.1.4.3.6], and monoamine oxidase [E.C.1.4.3.4] under its two isoforms, MAO A and MAO B, has been assessed. The substrate specifities of MAO and SSAO overlap to some extent. In this context, the search of new molecules, able to discriminate between these different amine oxidases is very important as it will allow greater elucidation of the SSAO’s role in physiological and pathological conditions. We report for the first time, the synthesis and evaluation of a new molecule which has a high affinity towards the SSAO family of enzymes, more so than previously described and furthermore an ability to discriminate between the different amine oxidases. # 2003 Elsevier Ltd. All rights reserved. 1. Introduction The term semicarbazide sensitive amine oxidase (SSAO) is used to describe a group of enzymes that catalyse the oxidative deamination of aliphatic and aromatic primary amines. They are classificated as E.C.1.4.3.6 (amine: oxygen oxidoreductase (deaminating) (copper-contain- ing), and all of them have 2,4,5-trihydroxyphenylalanine (TPQ) as cofactor. Semicarbazide is frequently used to distinguish the SSAOs from the monoamine oxidase, [amine: oxygen oxidoreductase (deaminating) (flavin- containing), E.C.1.4.3.4; MAO], that contains flavin adenine dinucleotide (FAD) as cofactor and are sensitive to acetylenic inhibitors such as clorgyline and l-deprenyl, but are not affected by semicarbazide. The substrate spe- cificities of MAO-A and SSAO overlap to some extent but, whereas MAO catalyses the oxidative deamination of primary, secondary and tertiary amines, SSAO activity appears to be restricted to primary amines. At present methylamine, which arises from the metabolism of adrenaline, lecithin, sarcosine, and creatinine, is the only physiological substrate known that can dis- criminate between both amine oxidases. Methylamine is exclusively metabolised by SSAO from many sources 1,2 and does not interact with MAO. Both enzymes catalyse the oxidative deamination of amines to ammonia, hydrogen peroxide and the corresponding aldehyde, according to the overall reaction: RCH 2 NH 2 þ O 2 þ H 2 O )þRCHO þ NH 3 þ H 2 O 2 SSAO is tightly associated with membranes in several mammalian tissues and also occurs as a soluble form in blood plasma. 3,4 The membrane-bound SSAO shows high activity in vascular tissue and it appears to be associated with smooth muscle cells. 5,6 SSAO activity has been also found in other non-vascular cell types such as chondrocytes, 7 bovine eye, 8 in dental pulp, 9 and in adipocytes from rat white and brown fat. 10 The physiological role of SSAO is still far from clear, despite its wide distribution in mammalian tissues. 11 SSAO located in the plasma membrane may act as a scavenger of circulating toxic amines and in this context, the enzyme present in the microsomal fraction of human and bovine lung 12,13 may be important in inhaled vola- tile amines metabolism. 14 This enzyme could also be involved in the control of cellular activities through the generation of H 2 O 2 . 15 It has been recently reported that SSAO co-localizes with GLUT4 glucose transporter in endosomal compartment in rat adipocytes and that SSAO substrates cause a marked stimulation of glucose transport, mimicking the effects of insulin. 16 0968-0896/$ - see front matter # 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmc.2003.10.007 Bioorganic & Medicinal Chemistry 12 (2004) 273–279 Keywords: 4-Methyl-thio-phenyl-propylamine; Synthesis; Biological evaluation; Amine oxidases inhibitor; SSAO; MAO. *Corresponding author. Tel.: +34-93-581-1523; fax: +34-93-581- 1573; e-mail: mercedes.unzeta@uab.es