Pharmacological and Therapeutic Profiling in Drug Innovation: The Early History of the Beta Blockers

PERSPECTIVES IN BIOLOGY AND MEDICINE Volume 31 ¦ Number 4 · Summer 1988 PHARMACOLOGICAL AND THERAPEUTIC PROFILING IN DRUG INNOVATION: THE EARLY HISTORY OF THE BETA BLOCKERS REIN VOS* and HENK BODEWITZf Introduction Drug innovation is commonly described as an interaction between basic academic and industrial research. The nature of this interaction, however, is differently appreciated. One view assumes that basic research directs industrial research, that academic scientists open up new perspectives leading to new drug development. According to this view, the dichotomy "basic-applied" is sometimes used as synonymous with "academic-industrial." Another view considers basic and industrial research as two distinct types of research, each with its own dynamics but continuously interacting to find new pathways of communication and collaboration. However, both views share the assumption that drug innovation involves the flow of ideas from research laboratories (academic or industrial ) into the various medical professional settings, with therapeutic practice determining the success ofthese ideas. The consequences of this way of analyzing drug innovation are twofold. First, this view neglects the possibility that the therapeutic context acts as an important stimulus to innovative drug research. Second, this way of analyzing drug innovation underestimates the extent to which clinical research contributes to ?Department of Pharmacology and Pharmacotherapeutics, State University of Groningen , 9713 AW Groningen, Antonius Deusinglaan 2, The Netherlands. tResearch Manager, Science Studies Program, State University of Groningen.© 1988 by The University of Chicago. AU rights reserved. 0031-5982/88/3104-0588$01.00 Perspectives in Biology and Medicine, 31, 4 · Summer 1988 \ 469 our knowledge of drugs and of the pathophysiological condition to be treated. By using the story of the development of beta blockers, we shall develop the view that both clinical research and the therapeutic context are integrally involved in drug innovation. This construction will be illustrated by an analysis of the early history of the beta-adrenoceptor blocking agents, a class of drugs that became an important breakthrough in cardiovascular treatment during the 1960s and 1970s. Historical Overview of the Development ofBeta Blockers The catecholamines, noradrenaline and adrenaline, are key regulators of many physiological processes in man. As we now know, noradrenaline acts primarily as a neurotransmitter released from sympathetic nerve terminals, and adrenaline functions as a circulating hormone released from the adrenal medulla. These catecholamines then interact with receptors in the tissues, and the end result of the transmitterreceptor interaction is the biological response of the tissue. Electrical stimulation of sympathetic nerves as well as injected catecholamines, for example, (nor)adrenaline-like compounds, produce their effects in the same way. The concept that catecholamines bind to specific receptors in various tissues, that this binding initiates the physiological response, and that there are two types of tissue receptors, excitatory and inhibitory, was first suggested by Langley in 1905 [I]. However, most historical reviews of beta blockers start with Sir Henry Dale's experimental work. Dale (1906) observed that, while the excitatory actions of adrenaline, for example, vasoconstriction and contraction of smooth muscle in other tissues, were blocked by ergot alkaloids, the inhibitory effects like vasodilatation and relaxation of bronchial muscle in the lungs were not [2]. Thus he provided evidence for Langley's hypothesis. It remained for Ahlquist (1948) to propose a new receptor classification [3]. He differentiated between two adrenoceptor populations by their responses in a variety of tissues. Ahlquist found only two orders of potency and therefore proposed the existence of two types ofadrenergic receptors that he named alpha and beta. In general, stimulation ofalpha receptors resulted in such excitatory physiological responses as vasoconstriction and contraction of smooth muscle in various tissues, while beta receptor stimulation resulted in the inhibitory responses, vasodilatation, bronchiolar muscle relaxation, and relaxation of the womb. A crucial exception to this general rule was in the heart. Cardiac excitatory responses , the increase in rate and force of contraction, were attributed by Ahlquist to the beta receptors. In this way Ahlquist classified cardiac excitatory responses along with the inhibitory responses of other tissues. Since at that time drug-receptor interactions at the cell level were poorly 470 I Rein Vos and Henk Bodewitz · Drug Innovation understood, the significance of Alilquist's contribution was that he proposed an operational classification in which the cardiac...