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PDF hosted at the Radboud Repository of the Radboud University Nijmegen The following full text is a publisher's version. For additional information about this publication click this link. http://hdl.handle.net/2066/113046 Please be advised that this information was generated on 2021-10-08 and may be subject to change. PHARMACODYNAMICS OF CHOLINOMIMETIC AND CHOLINOLYTIC DRUGS J. M. VAN ROSSUM L PHARMACODYNAMICS OF CHOLINOMIMETIC AND CHOLINOLYTIC DRUGS THEORIES ON DRUG-RECEPTOR INTERACTIONS AND STRUCTURE-ACTION RELATIONSHIPS OF QUATERNARY AMMONIUM SALTS Promotor Prof. Dr. E. J. ARIËNS Pharmacological Institute R.C. University Kapittelweg 40, Nijmegen. PHARMACODYNAMICS F CHOLINOMIMETIC AND CHOLINOLYTIC DRUGS THEORIES ON DRUG-RECEPTOR INTERACTIONS AND STRUCTURE-ACTION RELATIONSHIPS OF QUATERNARY AMMONIUM SALTS ACADEMISCH PROEFSCHRIFT TER VERKRIJGING VAN DE GRAAD VAN DOCTOR IN DE WIS- EN NATUURKUNDE AAN DE R.K. UNIVERSITEIT TE NIJMEGEN, OP GEZAG VAN DE RECTOR MAGNIFICUS DR. W.K.M. GROSSOUW, HOOGLERAAR IN DE FACULTEIT DER GODGELEERD HEID, VOLGENS BESLUIT VAN DE SENAAT DER R.K. UNIVERSITEIT IN HET OPENBAAR TE VERDEDIGEN OP VRIJDAG 14 MAART 1958 DES NAMIDDAGS TE 4 UUR DOOR JACOBUS MARIA VAN ROSSUM GEBOREN TE BERGHEM N.B. PRINTED BY THE ST. CATHERINE PRESS, LTD., BRUGES, BELGIUM 1958 Dedicated to my Mother, to the memory of my Father and to Maria. CONTENTS INTRODUCTION 11 Ι. — THEORIES ON DRUG ACTIONS 13 Introduction 13 Receptor-occupancy 15 Relationship between number of receptors occupied and effect . 18 Interaction of a single drug with several receptor systems ... 25 Competitive interaction 30 Competitive interaction and auto-interaction 38 Irreversible competitive interaction 40 Non-competitive interaction 43 Non-competitive interaction and non-competitive auto- interaction 51 Non-competitive interaction and functional auto-interaction . 52 Dualism in antagonism 53 Functional interaction 55 Discussion 57 References 59 II. — PHARMACODYNAMICS OF DRUGS AFFECTING SKELETAL MUSCLE 62 Introduction 62 Methods and materials 65 Experiments with the frog's rectus abdominis muscle .... 67 Experiments with nerve-muscle preparations 79 Discussion 81 Summary .· 82 References 83 III. — PHARMACODYNAMICS OF PARASYMPATHETIC DRUGS .... 87 Introduction 87 Parasympathetic drugs 88 9 Structure-action relationships 89 Methods and materials 92 Quaternary dioxolanes 94 Choline derivatives 100 Alkyltrimethylammonium salts 100 Non-competitive interaction 103 Functional interaction 105 Slope of the curves .107 Non-reversibility 107 Discussion 109 Summary in References 112 IV. — PHARMACODYNAMICS OF DRUGS AFFECTING BLOOD PRESSURE 116 Introduction 116 Methods and materials 118 Parasympathetic drugs on the isolated frog heart 119 Experiments on the cat's blood pressure 122 Experiments with the frog's rectus muscle 129 Discussion 131 Summary 133 References 134 V. — SYNTHESIS OF QUATERNARY AMMONIUM SALTS 136 Introduction 136 Decamethonium derivatives 136 Dicarboxylic acid bis-2-(trialkylammonium) ethylamides. 138 Racet drugs 140 Quaternary dioxolanes 142 References 147 SUMMARY 150 SAMENVATTING 155 10 INTRODUCTION Living organism and modern techniques make use of regulation mechanisms (WIENER 1950, WAGNER 1954). As evolution proceeds the number and complexity of regulation mechanisms in organisms increases. In the various regulation mechanisms, messages are carried along circuits in a humoral or neural way. Both in humoral and in neural transmission of messages chemical substances (e.g. transmitters) are involved. It is possible to influence transmission and thereby regulation mechanisms by compounds resembling to some extent the transmitting substance and which therefore interfere with the action of the transmitters. Such compounds have been derived from hormones, neurohormones, vitamins etc. It has also been found that naturally-occuring substances of plant origin, such as atropine and muscarine, do in fact resemble transmitting substances. Substances either of natural or synthetic origin have been found accidentally which do not chemically resemble any biologically active substance, but which nevertheless have a specific effect upon biological specimens, e.g. digitoxin and barbiturates. Substances which exert a ,1 , Ί '9 * »«•»· autonomic actions central ,1 P»S pits. nervous Ί system m nj _ motor action) FIG. 1 Strongly simplified block scheme for the regulation of autonomic and motor actions. In the heavy blocks acetylcholine is involved as a transmitting substance. These are the myoneural junction (m.m.j.), the sympathetic and parasympathetic ganglia (s.g. and p.s.g.) and the parasympathetic end-synapse (p.s.e.s.). In the sympathetic end-synapse (s.e.s.) arterenol acts as a transmitter. II specific effect upon an organism are called drugs, irrespective of whether or not they are of therapeutic use. The study of structure-action relationships and of the mechanism of action of drugs is only possible if theory and experiment go hand in hand. Theories concerning drug actions, as well as extensions thereof, are given first. On the basis of the theories of drug actions, the pharmacodynamics of cholinomimetic and cholinolytic drugs is studied. Since both cholino mimetics and cholinolytics resemble acetylcholine to some extent, they may interfere in those stages of biological regulation mechanism where acetylcholine operates under physiological conditions. As may be seen from figure i, acetylcholine is the transmitter substance in various parts of the peripheral nervous system. For this reason the following distinctions are made. a) Pharmacodynamics of cholinomimetic and cholinolytic drugs at the level of receptors in the myoneural junction, and in general drugs affecting skeletal muscle. b) Pharmacodynamics of cholinomimetic and cholinolytic drugs at the level of receptors in the parasympathetic nervous system, especially drugs affecting intestinal smooth muscle. c) Pharmacodynamics of cholinomimetic and cholinolytic drugs at the level of receptors, concerned with heart action and blood pressure. This includes the ACh receptors in the sympathetic and parasym pathetic ganglia and in the parasympathetic end-synapse. The drugs used as cholinomimetics and cholinolytics at the different ACh-receptors are quaternary ammonium salts. REFERENCES WIENER, N. Cybernetics (1950). Ed. J. Wiley and Sons Inc., New York. WAGNER, R. Probleme und Beispiele biologischer Regulierung (1954). Ed. G. Thieme Verlag, Stuttgart. 12 CHAPTER I THEORIES ON DRUG ACTIONS INTRODUCTION The study of concentration-response curves and time-response curves forms the foundation of a proper understanding of drug actions. The concentration-response curves express the relationship between the con centration of the drug applied and the effect obtained w ith the biological object. Generally this relationship underlies a chain of individual steps or reactions, which is schematically represented in figure i. „stimulus" W0 r 1 Mi , 2 3 (dose applied) (biophase) drug- specific transference receptors FIG. I Block scheme by which the sequence of events leading to the effect of a single drug, may be described. Block ι represents the relationship between the dose applied and the drug concentration in the biophase. The influences of transport, breakdown etc. are collected in this block. The reaction of drug molecules with the specific receptors is presented by block 2 A stimulus which is linearly proportional to the quantity of receptors occupied leaves block 2 and enters block 3. The relationship between the stimulus and the final effect is given by block 3. It is generally assumed that in order to produce an effect, drug mole cules have to interact with specific receptor molecules in the biological object. Receptor-occupancy is however, not necessarily the first step in the chain leading to the effect. In addition to the interaction of the drug molecules with their specific receptors, absorption, transport, breakdown ect. are of importance. The influence of these factors is collected in the first block of the scheme and designated as " drug- transference ". Generally the drug concentration [A], in the immediate vicinity of the receptors (i.e. in the biophase) is a function of the dose 13 applied (i.e. the concentration [A] 0 in the bath fluid for isolated organs). The use of simple isolated organs as a biological object for the experi ments may reduce the influence of absorption, transport, biotransfor mation etc. to a large extent. Then the drug concentration in the bio- phase often is a linear function of the concentration in the bath fluid. For instance there is a partition equilibrium according to Henry's law. Thus : [A],· = KA. [A]. (i) Here KAp is the partition equilibrium constant of drug A. Since the experiments are chiefly undertaken with isolated organs, in this thesis it is assumed that the concentration of the drug in the biophase is directly proportional to the dose of the drug applied. Hence attention is mainly called to the receptor-occupancy (block 2) and to the effect which is the result of it (block 3). In biochemistry, the mass law as introduced by MICHAELIS and MENTEN (1913) has been found useful. The introduction of the same principles for the drug receptor interaction proved to be of value for many pharmacological actions (See for instance CLARK 1937). It must be borne in mind that, although in some cases the receptors are enzymes, in fact they are often not known in any detail. The assumption of their existence is, however, essential for the molecular approach to drug actions.