J. P. M. Finberg, M. B. H. Youdim, P. Riederer, K. F. Tipton (eds.) MAO-The Mother of all Amine Oxidases Springer-Verlag Wien GmbH Prof. Dr. J. P. M. Finberg Prof. Dr. M. B. H. Youdim Department of Pharmacology, The Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel Prof. Dr. P. Riederer Clinical Neurochemistry, Department of Psychiatry, University of Würzburg, Federal Republic of Germany Prof. Dr. K. F. Tipton Biochemistry Department, Trinity College, Dublin, Ireland This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically those of translation, reprinting, re-use of illustrations, broadcasting, reproduction by photo copying machines or similar means, and storage in data banks. © 1998 Springer-Verlag Wien Originally published by Springer-Verlag Wien New York 1998 Product Liability: The publisher can give no guarantee for information about drug dosage and application thereof contained in this book. In every individual case the respective user must check its accuracy by consulting other pharmaceutical literature. The use of regis tered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and reg ulations and therefore free for general use. Printing: A. Holzhausens Nfg., A-1070 Wien Graphic design: Ecke Bonk Printed on acid-free and chlorine-free bleached paper SPIN: 10636439 With 76 (partly coloured) Figures ISBN 978-3-211-83037-6 ISBN 978-3-7091-6499-0 (eBook) DOI 10.1007/978-3-7091-6499-0 Preface The 6th Rappaport Symposium and 7th Amine Oxidase Workshop was held in lune 1996 at Shavei Zion, on the northern coast ofIsrael, some 25 km from the Lebanese border. In view of the tense security situation which preceded the symposium, the organisers are particularly grateful to all the participants for their support. lust one year before this conference we all learned of the death of our dear colleague, Dr Moise Da Prada, to whose memory this meeting was dedicated. Induded in these Proceedings are two appreciations of his life's work by dose colleagues. We were honoured to be able to host his widow, Maria Strauss-Da Prada, at the meeting and hope that all the Da Prada family receive comfort from this record to the memory of Moise, whose passing is such a loss to our field. He will be remembered for his kindness and exuber ance as weil for his scientific distinction and his steadfastness in promoting the therapeutic value of MAO inhibitors through aperiod when they had, temporarily, fallen into disfavour. The monoamine oxidases are enzymes which constantly produce surprises, and one of the aspects which we chose to highlight in the meeting was the recent discovery of patient groups bearing selective genetic deficiencies in MAO-A or MAO-B. The importance of such genetic alterations in the patho genesis of mental and neurological disorders is currently under debate. In particular, the possibility that selective MAO-A deficiency could be respon sible for violent behaviours in general was raised in the popular press immediately before the meeting, and we were happy to receive important con tributions from Drs. D. Murphy and H. Brunner and their groups which help to darify the situation. Another surprise in the MAO field has been the discovery of the neuro protective or neuro-rescuing actions of some propargyl-derivative MAO-B inhibitors, and the role ofMAO in oxidative stress. Such aspects are covered in several places within this book together with many other advances in our understanding ofthe structure, behaviour and functions ofthe amine oxidases. We hope this volume will be of value to all those wishing to learn about cur rent knowledge and opinions of the roles of the amine oxidases in health and disease. We wish to acknowledge with thanks the sponsorship and financial support ofthe following in enabling our meeting to take place: Rappaport Family Institute far Research in the Medical Sciences; Bruce VI Preface Rappaport Faculty of Medicine, Technion, Israel Institute of Technology; the International Union of Biochemistry and Molecular Biology (lnterest Group IG 156); Hoffman-La Roche Ud, Switzerland; Synthelabo Recherche (L.E.R.S), France; DeVries & Co Ud, Roche, Israel; Teva Pharmaceutical Industries Ud, Israel. J. P. M. Finberg M. B. H. Youdim P. Riederer K. F. Tipton Prof. Mose Da Prada 1934-1995 Mose Da Prada: Development ofan outstanding scientist A. Pletscher In 1963 Mose Da Prada became a member of my personal research group at Hoffmann-La Roche Basel. At that time, he did not have much research expe rience. Nevertheless, I decided to accept his application for a position in my group, because I was intrigued by his high motivation to enter the field of bio chemical pharmacology. Thus, I could closely follow his remarkable develop ment as a scientist and the rising recognition of his human qualities by his environment. These aspects will be briefly dealt with in the following. From Bologna to Basel Three circumstances were at the origin ofDa Prada's decision to leave his job as assistant at the Medical University Clinic of Bologna and to join our research group at Hoffmann-La Roche in Basel. Firstly, he was attracted by Roche's activities in the then new field of bio chemical neuropsychopharmacology. With its first, long acting, synthetic monoamine oxidase (MAO)-inhibitor, iproniazid, Roche had opened a new approach to the treatment of mental depression and had entered the field of biogenic monoamines. Da Prada, as a graduate in medicine and pharmacy, was much interested in these developments. A second attractor in Roche Basel was Mose's close friend Giuseppe Bar tholini, with whom he had been working in Bologna and who had joined our group about a year before. Bartholini very much liked the scientific approach es and the working facilities at·Roche. Since he was aware of the "scientific potential" of Mose, he wanted hirn to work with us and motivated hirn to join our group. A third reason for Da Prada's decision to leave Bologna was the unfavour ab1e research situation in the medical clinics of its university. Due to insuffi cient salaries, many of the young MD's had to earn their living by performing part-time private practice in addition to their daily clinical work. Also, the infrastructure for research was poor. This made serious scientific work impos sible. No wonder that a research-motivated young man like Da Prada tended to leave such a place. Thus, the decision ofMose Da Prada to change from Bologna to Basel was motivated by a "push and pull" situation. x A. Pletscher Scientific development During this stay in oUf group, two lines of research were in the center of Da Prada's activities, i.e. the biology of monoamines at the cellular and subcellu lar level and the action of neUfopsychotropic drugs on the monoaminergic sys tems of the central nervous system. Since, as already mentioned, he had no experience in biochemical pharmacology, I asked hirn to start work with isolat ed blood platelets, which were used in our laboratory as relatively simple, par tial models for certain aspects ofcerebral monoamine dynamies. The method ological skills ofMose soon became apparent. He developed chromatographie methods by which he clarified the metabolism of5-hydroxytryptamine (5-HT) in platelets and the effect ofdrugs, like reserpine, benzoquinolizines and phen ylalkylamines, on the formation ofmetabolites, e.g. 5-hydroxyindolacetic acid and 5-hydroxytryptophol. Later, Da Prada and Tranzer, using electron micros copy and biochemical techniques, played an essential role in the discovery of the intracellular storage sites of 5-HT in platelets of various species and in megakariocytes. Mose succeeded for the first time in isolating the 5-HT-stor age organelles (storage granules, dense bodies) in pure form by sophisticated fractionation methods. This allowed the direct elucidation of the action of drugs at the level of the storage organelles, showing, for instance, that reser pine exerts its effect at the granular membrane. The collaboration ofDa Prada with physico-chemists also led to the clarification of the intragranular storage mechanism of biogenie amines in platelets and chromaffine granules of the adrenal medulla. Their experiments presented evidence for the existence of polymerie complexes of the monoamines with the intragranular nucleotides like ATP, and in the case ofchromaffine granules, also with proteins. These findings, in which Da Prada played an essential role, helped to estab lish platelets as partial models for other tissues, including brain, with regard to monoamine uptake, storage and metabolism. The platelet model is still being used, especially in clinical studies. Later, Mose also proceeded to the central nervous system. His first activi ties in this field were devoted to the elucidation of the mode of action ofneu ropsychotropic drugs, in order to find clues for the design ofnovel compounds with therapeutic action. He started with work on neuroleptics and phenylethy lamines. These investigations, carried out together with his colleagues, helped to clarify the mechanism of action of chlorpromazine on cerebral dopamine metabolism. They also showed that phenylethylamines had different effects on cerebraI monoamines, depending on their substituents at the aromatic ring and the nitrogen ofthe side chain. For instance, methamphetamine, with a chlorine substituent in 4-position of the ring, caused a marked, specific decrease of cerebral 5-HT and 5-hydroxyindolacetic acid (indicating an inhibition of 5 HT-biosynthesis). Thus, the 4-chloro derivative has an effect similar to that of methylene-3,4-dioxymethamphetamine (MDMA, "ecstasy"), a derivative, missed in oUf series, which was discovered later by another group. Mose was now "grown up" and promoted to become head of his own Mose Da Prada: Development ofan outstanding scientist XI research group. Equipped with experience gained in his more basic work, he became engaged in the development ofnew drugs. His efforts were concentrat ed on MAO-inhibitors and anti-Parkinson-drugs, both elassical areas ofRoche research. With the members of his group, he created sophisticated screening tools, ineluding novel, highly sensitive and specific radioenzymatic tests for monoamines, which were soon also used by the international "monoamine community". With the help of these tests, potent and specific inhibitors of MAO-A and -B and catechol-3-0-methyltransferase (COMT) were discovered and developed in Da Prada's group. Several of these compounds show thera peutic actions in neuropsychiatric disorders. Moelobemide (inhibitor ofMAO A) is on the market as an antidepressant, Tolcapone (inhibitor of COMT) is being prepared for marketing as adjuvant in Parkinson's disease and Lazabe mide shows promising clinical effects in Alzheimer's disease. In all these achievements Mose played an essential role as creative spirit and leader ofthe experimental work, which got wide international recognition. These research activities will be reported in the following presentations. The human side The start in Basel was not easy for Mose. His move from the lovely south to the "barbaric" north brought changes in his personal life which were not all to his liking. He complained about the quality of food, the lack of sunshine, the unfriendliness ofthe people, etc. Thus, he did not appreciate the fines for traf fic violations, such as those imposed on hirn for making U-turns over double security lines with his Alfa Romeo. However, as time passed, Mose started to adapt to his new environment. His generous and friendly character and his readiness for collaboration helped hirn to establish friendly relations with many ofhis colleagues. Due to his rising recognition in the international scien tific community, he also attracted foreign collaborators, from his horne coun try, Italy, and from other parts ofthe world. Forthem he was not only an inspir ing and charismatic scientific leader, but he also showed great sympathy for their personal problems. Mose's hospitality was overwhelming, his fabulous laboratory parties. at which he offered the delicacies of his horne country, will certainly remain in our memories. The culmination in Mose's personal life was his late matrimonial union with Maria. In her he found a companion who showed great understanding for his work and whose love supported hirn in difficult situations, from which he was not spared. With Maria his successful adjustment to life in the north was accomplished. Nevertheless, Mose remained attached to his family in Italy. Above all, his elose connection with his brother Don Giovanni, a priest and well-known painter in Fusine, a village of the valley Valtellina, has to be mentioned. The brothers had many interests in common, e.g. their love for arts and literature. A sign of the high esteem which Mose enjoyed in the Valtellina was the crea-