With the compliments of BAYER AG, Research Department

With the compliments of BAYER AG, Research Department

W.-D. Busse B. Garthoff F. Seuter (Eds.) Dihydropyridines Progress in Pharmacology and Therapy With 53 Figures and 6 Tables Springer-Verlag Berlin Heidelberg New York London Paris Tokyo Hong Kong Barcelona Budapest

WOLF-DIETER BUSSE, Ph.D., Professor International Research Pharma BAYERAG Aprather Weg 18 a 42096 Wuppertal Germany BERNWARD GARTHOFF, DVM Cardiovascular and Arteriosclerosis Research BAYERAG Aprather Weg 18 a 42096 Wuppertal Germany FRIEDEL SEUTER, Ph.D. Coordination International Research BAYERAG Aprather Weg 18 a 42096 Wuppertal Germany ISBN-13: 978-3-540-57308-1 e-isbn-13: 978-3-642-95716-1 DOl: 10.1007/978-3-642-95716-1 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer-Verlag. Violations are liable for prosecution under the German Copyright Law. Springer-Verlag Berlin Heidelberg 1993 The use of general descriptive names, registered 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 regulations and therefore free for general use. Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting the relevant literature. Typesetting: Best-set Typesetter Ltd., Hong Kong 27/3130/SPS-5 4 3 2 1 0 - Printed on acid-free paper

Preface At the Pharmacology Workshop held in Wuppertal on December 11, 1992, Dr. Alexander Scriabine was honored for his contribution to drug development at our company. Dr. Scriabine was the first pharmacologist to join Miles in West Haven, CT, in 1979. He established the Miles Institute for Preclinical Pharmacology, at the Yale campus, which was devoted to cardiovascular, metabolic and, later, CNS research. At that time Ca 2 + antagonists were not yet available in the USA, but well established in Europe. At Bayer, Bossert and Vater discovered 1,4-dihydropyridines in the late 1960s, and Fleckenstein identified nifedipine as the most potent Ca 2 + antagonist available at that time. This discovery led to the establishment of Ca 2 + antagonists as leading cardiovascular drugs throughout the world and to the marketing of nifedipine as Adalat by Bayer. The main function of the Miles Institute for Preclinical Pharmacology was the introduction of Bayer Ca 2 + antagonists to the American scientific community. Scriabine, in collaboration with Stanislav Kazda and Bernward Garthoff, contributed numerous publications on the pharmacology of Bayer Ca 2 + antagonists, supported many collaborative studies with extramural investigators in the USA, and organized several international conferences on Ca 2 + antagonists. These conferences contributed to the recognition of the importance of these drugs for the treatment of hypertension and coronary heart disease in North America. Scriabine and his colleagues were also instrumental in the introduction of new technology for evaluating Ca 2 + antagonists and other drugs. The first electrophysiology laboratory in the pharmaceutical industry was established at the Miles Institute for Preclinical Pharmacology by Charles Cohen and Richard McCarthy, and dihydropyridine receptors were characterized in a collaborative study between Ronald Janis of Miles and David Triggle of the State University of New York at Buffalo. With the help of electrophysiological techniques, Richard McCarthy succeeded in demonstrating the effectiveness of Ca2+ antagonists at the single cell level. This technique was used to demonstrate direct neuronal action of nimodipine, a calcium antagonist discovered by Horst Meyer, Stanislav Kazda, and Friedrich Hoffmeister. Numerous pharmacological studies were undertaken at the Miles Institute for Preclinical Pharmacology,

VI Preface such as with BAY K 8644, a Ca 2 + agonist, discovered by Matthias Schramm in Wuppertal. This symposium reviews important milestones in the history of the development of 1,4-dihydropyridines as Ca 2 + antagonists and includes presentations of the results of some recent collaborative extramural studies by American investigators. Wuppertal, September 1993 WOLF-DIETER BUSSE

Contents Twenty Years of Dihydropyridines S. KAZDA (With 5 Figures)...................................... 1 1,4-Dihydropyridines and the 1,4-Dihydropyridine Receptor D.J. TRIGGLE (With 3 Figures)................................... 13 l,4-dihydropyridines: Effects of Chirality and Conformation on Their Activity S. GOLDMANN and J. STOLTEFUSS (With 9 Figures).................. 24 Pharmacological Classification of High-Threshold Calcium Channels in Rat Neurons B.P. BEAN and I.M. MINTZ (With 7 Figures)....................... 36 Effects of Dihydropyridine Calcium Antagonists upon Microvascular Function Following Ischemia and Oxidative Stress J.A. WATTS (With 5 Figures)... 46 Calcium Agonists R. GROSS, M. BECHEM, S. HEBISCH, P. ROUNDING, and M. SCHRAMM (With 9 Figures)............................................... 60 Nimodipine and Nervous System Function J. TRABER, F.J. VAN DER STAAY, and J. DE VRY (With 4 Figures)....... 71 Nimodipine and Learning in Aging Rabbits J.F. DISTERHOFT, J.R. MOYER JR., L.T. THOMPSON, and M. KOWALSKA (With 5 Figures)............................................... 81 Molecular Biology of Calcium Channels P. SPREYER, J.K. FRANZ, A. ELLER, P. RAE, and A. UNTERBECK (With 3 Figures)............................................... 98

VIII Contents From the Cardiovascular to the Central Nervous System An Adventure in the Pharmacology of Dihydropyridines A. SCRIABINE (With 3 Figures).................................. 111 At the End of this Workshop - Final Remarks B. GARTH OFF.................................................. 119

List of Authors BEAN, B.P. Department of Neurobiology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA BECHEM, M. BUSSE, W.-D. BAYER AG, International Research Pharma, P.O. Box 10 1709, Aprather Weg 18a, 42096 Wuppertal, Germany DrSTERHOFT, J.F. Department of Cell, Molecular, and Structural Biology, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, IL 60611-3008, USA ELLER, A. BA YER AG, Cardiovascular and Arteriosclerosis Research, P.O. Box 10 1709, 42096 Wuppertal, Germany FRANZ, J.K. GARTHOFF, B. BA YER AG, Cardiovascular and Arteriosclerosis Research, P.O. Box GOLDMANN, S. BAYER AG, Pharma Research, Chemistry Department, P.O. Box 10 1709, 42096 Wuppertal, Germany

x List of Authors GROSS, R. HEBISCH, S. 101709,42096 Wuppertal, Germany HOnER, J. 10 17 09, 42096 Wuppertal, Germany KAZDA, S. KOWALSKA, M. Department of Cell, Molecular, and Structural Biology, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, IL 60611-3008, USA MINTZ,I.M. Department of Neurobiology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA MOYER JR, J.R. Department of Cell, Molecular, and Structural Biology, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, IL 60611-3008, USA RAE, P. 10 1709,42096 Wuppertal, Germany and Miles Research Center, 400 Morgan Lane, West Haven, CT 06516, USA ROUNDING, P. SCHRAMM, M.

List of Authors XI SCRIABINE, A. Miles Institute for Preclinical Pharmacology, 400 Morgan Lane, West Haven, CT 06516, USA SPREYER, P. STAAY, F.J. VAN DER BA YER-Tropon Institute for Neurobiology, Troponwerke, Berliner Str. 156, 51063 Cologne, Germany STOLTEFUSS, J. BAYER AG, Pharma Research, Chemistry Department, P.O. Box 10 17 09, 42096 Wuppertal, Germany THOMPSON, L. T. Department of Cell, Molecular, and Structural Biology, Northwestern University Medical School, Chicago, 303 East Chicago Avenue, IL 60611-3008, USA TRABER, J. BAYER-Tropon Institute for Neurobiology, Troponwerke, Berliner Str. 156, 51063 Cologne, Germany TRiGGLE, D.J. School of Pharmacy, State University of New York, Buffalo, NY 14260, USA UNTERBECK, A. and Miles Research Center, 400 Morgan Lane, West Haven, CT 06516, USA VRY, J. DE BA YER-Tropon Institute for Neurobiology, Troponwerke, Berliner Str. 156, 51063 Cologne, Germany WATTS, J.A. Department of Biology, University of North Carolina "at Charlotte, NC 28223, USA Charlotte,