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In praise of nitroglycerin - a celebrated centenary
77P.S - November I980
428
In praise of nitroglycerin a celebrated centmary James R. Parratt Exactiy one hundred years ago last year saw the introduction of glyceryl trinitrate (nitroglycerin) as a therapeutic agent for the prevention and treatment of angina pectoris. One wonders how many other dr;gs have been as extensively and successfully used for so long and whether, despite the enormous advances in drug design and testing, such a drug could ever have been discovered by the pharmaceutical industry. This essay will attempt to show that. if a research director in a pharmaceutical company with a knowledge and understanding of the angina syndrome was to set himself the task of designing, on pathophyGological grounds. an ‘ideal’ antianginal drug, he would finish up with a substance bearing a remarkable resemblance to nitroglycerin. He would doubtless be hailed as a pharmacological genius and, if he were British. would almost certainly be elected to a WIlowship of the Royal Society. To fulfil this task such a man would fit need to possess a clear understanding of the pathophysiology of angina pectoris and he could do no better. in the first instance. than to return to Heberden’s classic derription given to the London College of Physicians in 1768 and published, in the lwe&rl Tmmactiom of the College, in 1772. He described ;ihe condition as ‘a disorder of the breast marked with strong and peculiar symptoms, considerable for the kind of danger belcnging to it and nut erJremely rare. The seat of it and sense cf strangling, and an&y with which it is artended, may make it not improperly be called angina pectoris’. He accurately described the locaticn of the pain, noted that ‘makes are most liable lo this disease, especiail) such as hate pawed their fiieth year, have short necks ;Ind ~srclineto be fat’ and drew attention to tne fact that the pain is bmught on by exe&*,- (‘they who are affhcted with it are setid while they are walking, more especially if it bc up a hill’) and by cxccciternent,anxiety (‘any disturbance of mind’) and eating. Apparently the latter is particularly true in certain parts of E tl=WrlNuEbrb(lnd BKlavdrpl
Press ,980
the United States. It has been suggested that this is due to the habit of drinking iced water and smoking between courses. Heberden also noted that the pain often disappeared on stoppmg the exercise (‘the moment they stand still all this uneasiness vanishes’) and later drew attention to the seriousness of the condition (‘the termination is remarkable. the patients all suddenly fall down. anti perish almost immediately’). This is a classic description of sudden cardiac death (ventricular fibrillation) resulting from an acute myocardial infarction. Our hypothetical research director would then take note of Bum’s finding in 1809 that ‘in dl patients that have died of Syncope Anginosa, the coronary arteries have either been found ossified or cartilaginous’ and would doubtless also take cognizance of the recent ( 1977) survey by Roberts Jnd Spray that ‘all (anginal) patients on necropsy showed a greater than 75% narrowing of the left anterior descending coronary artery by atheromatous plaques and that almost all (96% and 78% respectively) have a similar severe narrowing of the right wronary artery and of the left circumflex branch’. He would however also discover (mainly from the extensive studies of Maseri’s group in Pisa and now in London) that there are really two kinds of angina: the majority have a reduced coronary artery lumen due to atheroma but a significant number (perhaps IO-20% of all angina1 patients) have typical chest pain but essentially normal coronary arteries. His conclusion might w~ellbe that this form of angina, due to coronary vasospasm, might be amenable to coronary vasodilator drugs (as was outlined in a recent issue of TIPS by Imai’) but that ‘c\assicat’ angina ,would not be improved by drugs with a predominant dilator action on coronary arterioles. He might, I think correctly, surmise that if there were a major obstruction in the main supplying vessels, the heart would respond by dilatation of the resistance vessels (the
arterioles) distal to the obstruction and that to design drugs with a predominant action at this particular site within the coronary circulation might not be especially helpful. I think that it is at this point that our research director might. quite legitimately, decide that there was very little future in the exercise and switch his attention to ‘designing’ yet another @adrenoceptor blocking agent. If he persevered however. he would discover that another approach to the problem was open to him. This would depend upon his understanding of the haemodynamic responses preceding anginal pain. If he did he would have learnt a most important lesson. namely that a clear understanding of the pathophysiology of a disease state is fundamental to any attempt to design drugs for that condition. Angina is really a form of acute, reversible. ventricular failure. This has been detailed demonstrated by clearly haemodynamic investigations in patients subjected either to exercise (treadmill or bicycle ergometer) or to electrical intracardiac pacing such that the heart rate is increased to levels similar to those observed in exercise. If the lumen of the left ventricle is also catheterized. and pressure recorded, it can be shown that pacing leads to an abnormal increase in left ventricular end-diastolic (filling) pressure (LVEDP) and this is also reflected in elevated pulmonary artery and pulmonary wedge pressures. LVJZDP can increase to levels as hiih as 40 mmHg in patients with angina; the range for normal subjects during exercise is 8-l 0 mmHg. This abnormal increase in fiiing pressure (and volume) is partly due to a reduced myocardial compliance (or ‘give’). It is not accompanied by a parallel increase in stroke volume, and left ventricular function curves are shifted downwards and to the right. There are two main consequences of this abnormal elevation in filling pressure (Fig. 1). Firstly, there is an increase in myocardial wall tension, that is an increased stretch of the cardiac muscle fibres at rest. This often, although not always, leads to an increase in cardiac size; either way, myocardial orvgep demands would be increased. The other consequence is underpcrfusion of the deeper (endocardial) regions of the ventricular wall, a phenomenon admirabiy described 3s the ‘diastolic crunch’, Fig. 1 shows how this arises and also reveals that there might be three possible pharmacological approaches to alleviating this problem: (1) A crrr&rc s&u&r~ might alleviate the condition and our research director
tnight, againlegitimately. draw the parallel with the stt~t~on in chronic cardiac failure and its alhviation with digitalis glycosidea. He might decide that if he could reduce heart size and myocardial wall tension (important determinants of rarai myocardial oxygen consumption) this decrease in oxygen rsquirements might outweigh an increase demanded by the improved myocardial contractility. (2) A second approach would be to attempt to reduce the gross& elevated ventricular filling pressure by an increnrp in venouf ru~~~ce. lfour director was also a medical historian he would pmbably remember that Lauder Brunton in 1867 drew attention to the fact that angina1 pain could be reduced by bleeding (‘small bleedings of three or four ounces by venesection were alwrjseffective’). The obvious way to achieve this by pharmacological means would be to search for dilator drugs which were more effective on venous smooth rmtscle than elsewhere within the peripheral vascular bed. One way that this could be examined would be to set up isolated preparations of the circufarly arranged smooth muscle from ~~~~ral
veins and artcries Our now mcreasingl) aware director would discover. perhaps to his surprise. that wrne dilator {and constrictor) drugs dkz indeed have an almost selective effect on venous as opposed to arterial or, more important. arteriolar smooth muscle’. The administration of such a compound would prevent the nbnormal increase in left ventricular filling pressure and end-diastolic volume observed in angina1 patients on exertion; chest pain would thus be relieved because of the reduced myocardial oxygen demarids and the removal of the ‘diastolic crunch’. Although to produce a drug possessing both These particular pharmacological properties would be a major advance our ‘ideal director’ might feel he could gild his golden drug wtth another precious layer of pharmacological activity. Looking again at Fig. I he might decide that it would probably be useful if his drug possessed: (3) the capacity to ddate the large intramural arteries running at right angles through the ventricular wall from the major supplying epicardial vessels to the su~nd~ard~l plexus. This woutd be a
‘selective’ effect on the larger coronar) vessels 9s opposed to a general corf3nary (arteriofar) vasodiiator action. it could bc argued that such an effect would result ii increased endocardial perfusion and an increase in the rndolepi blood flop ratio. Such a dw would have the added advantage of being suitable for the treatment of variant angina since it would al%, relieve large coronary artery spasm. There are other properties that could be buiIt into our ‘ideal’ antianginal drug. It could be cirgued for example that to interfere with the perception of pain at the level of the central nervous system might be beneficial and that if the individual anginai patient was unfortunate enough (many do) to develop a? some time an acute myocardial infarction. an antidysrh! thmic action and an abil$ to reduce the area of ischaemic damage might alscr be helpful. The board of management to ahorn our hypothetical research director was responsible might be forgiven for belicring that such a dmg could not be designed or produced. Of course. with existing techniques for screening and discovering prospective antianginal agents. the) Hould probabl) be
Diastolic pmsaum 80 mmHg \
Lumen
obstrucrea
athemmatouo
by
Prawn2
Oiiolic pressuredistal
\
;* SLbendclcardiil Parfuslon Pressufe =80-5=
75mmHg
During
angina LMDP
SEDP
=&l-30
= 30 mmng
: lOmmt(g
to
7YP.S-November
430 right. However the almost unbelievable fact is that such a drug actually exists and indeed has been used successfully in the therapy of angina for a hundred ~SUS. Nitroglycerin really is a most remarkable drug. It was discovered, you will observe, not through the chemical tinkerings of an existing active nucleus. or through an examin+ tion of that ‘basic law’ of drug development the ‘structure-activity relationship’ (nor even through application of the Hansch analysis) but through the stroke of genius of a busy physician with a clear and basic understanding of circulatory physiology. William Murrell, when he surmised in 1879. that, ‘from a consideration of the physiclogical [we would today say pharmacological] action of the drug it would probilbly be of value in the treatment of angina”. probably laid claims to be the first clinical pharmacologist. James Black. many years later. wrote in similar vein about the idea that fiblocking drugs might
be valuable in the treatment of the same pathological condition. I wonder whether perhaps he had studied Murrell’s original Lancer paper. What Murrell unfortunately did not foresee was that his drug might also be useful in another condition, one from which he himself died in June 1’912. For the latest saga in the history of this remarkable ‘centenarian’ is that, as with other peripheral vasodilators. nitroglycerin is also of value in decreasing pre (and after) load in congestive heart failure’. I salute- a truly remarkable drug.
Readlhlgllst 1
1.07439 (I 977) Sr. 1.
Imai, S. ( 1979) 7iend~ fharmac01. Sri.
2 Mackenlie. J. II. and Parratt, J. R. PharmuvI. ho. 1M-1 60 3 Murrell.W.(1679)1~nc~ri.81~1 4 Parrart. J. R. k.1979) 1. Phwm. 801409
Phamcol.
3 I.
Wndina enerav alpdthe excitatjon of~ormone receptors _
_
T. J. Franklin Depwmenr of Siochemistq~, ICI L Id.. Mvrside. Aide&y
The 1970s saw an enormously increased interest in the biochemistry of hormone receptors. The availability of many radiolabelled drugs and hormones made receptor binding studies one of the more popular and fruitful activities in biochemical pharmacology. Receptor: whose excitation is closely olupled to an easily measured bitixhemical response, such as increased cyclic AMP synthesis, are especially attractive objects of study because the action of hormones and synthetic analogues on the biochemical responses can be usefully compared with the results of the receptor binding studies. A fascinating and complex picture has emerged of the biochemical mechanisms which couple the excitation of certain receptors to the stimulation of r;denylate cyclase’. Whilst progress in elucidating the biti hemical evems associated with the excitation of otber types of receptors has been less exhilarating, there is no doubt that receptor excitation is a remarkably effective trigger that initiates the biochemical changes which result in the characteristq.c biological response. C EbcvrrlSmbIfdhd BiancdiralPree I 9811
I980
Park. ~ia.cch*s~e~d.Cbeshire SKI0 4TG. U.K.
in complete contrast we know little 0:’ nothing about the molecular mechanisms of receptor excitation itself or of the details of the interactions between hormones anrl their receptors. How do agonists excicc their receptors? What is the molecular basis for the e:Eficacy of partial agonist!? Why are some competitive antagonists of hormones enti;ely without agonist activity? Pharmacologists have puzzled over these questions for decades and precise answers znwit the elucidation of the molecular anatomy of receptors, their specialized m&environments and the conformatiohai structures of excitatory and inhibitory ligands as they bind to their receptors. In the meantime we can speculate in the hope that our !;peculations suggest experiments that may help towards understanding. A major hindrance to scientific progress in the late twentieth century is the compartmentation of ideas that results from extreme specialization. For example, investigators of receptor pharmacology do not, in general, spend much time with enzymologistsconcerned with the mechan-
isms of enzyme catalysis. In an attempt at bridge building, I hope to show in this commentary that one of the ;nost important current concepts in molecular enzymology may have major implication for our eventual understanding of th,* nature of the efficacy of agonis.,, BIIing energy and enzyme catalysis A few years ago in a classic review, W. P. JencksZ analysed the contribution of the intru,ric free binding energy, AGIS.L. released when a substrate binds to the active site of an enzyme, to the efficiency of the catalytic process. He noted that the Michaelis constants, Km, of many very specific substrates are remarkably high, i.e. between 0.1 and 0.01 mM. If the Km value measures the affinity of a substrate for its enzyme. such values suggest relatively weak binding, a conclusion apparently at odds with the exquisite specificity of many interactions. Jencks enzyme-substrate resolved this contradiction by proposing that part of the intrinsic free energy of binding is used to ‘pay’ for the efficiency of catalysis. Transition state theory holds that enzymic catalysis depends essentially upon the ability of enzymes to lower the free energy of activation to achieve the transition state intermediate (Fig. 1). In the absence of the specific enzyme, a reaction such as: A+(B)
+c
where (B) is the transition state intermediate between the substrate, A, and the product, C, will be very slow if the energy bar-
428
In praise of nitroglycerin a celebrated centmary James R. Parratt Exactiy one hundred years ago last year saw the introduction of glyceryl trinitrate (nitroglycerin) as a therapeutic agent for the prevention and treatment of angina pectoris. One wonders how many other dr;gs have been as extensively and successfully used for so long and whether, despite the enormous advances in drug design and testing, such a drug could ever have been discovered by the pharmaceutical industry. This essay will attempt to show that. if a research director in a pharmaceutical company with a knowledge and understanding of the angina syndrome was to set himself the task of designing, on pathophyGological grounds. an ‘ideal’ antianginal drug, he would finish up with a substance bearing a remarkable resemblance to nitroglycerin. He would doubtless be hailed as a pharmacological genius and, if he were British. would almost certainly be elected to a WIlowship of the Royal Society. To fulfil this task such a man would fit need to possess a clear understanding of the pathophysiology of angina pectoris and he could do no better. in the first instance. than to return to Heberden’s classic derription given to the London College of Physicians in 1768 and published, in the lwe&rl Tmmactiom of the College, in 1772. He described ;ihe condition as ‘a disorder of the breast marked with strong and peculiar symptoms, considerable for the kind of danger belcnging to it and nut erJremely rare. The seat of it and sense cf strangling, and an&y with which it is artended, may make it not improperly be called angina pectoris’. He accurately described the locaticn of the pain, noted that ‘makes are most liable lo this disease, especiail) such as hate pawed their fiieth year, have short necks ;Ind ~srclineto be fat’ and drew attention to tne fact that the pain is bmught on by exe&*,- (‘they who are affhcted with it are setid while they are walking, more especially if it bc up a hill’) and by cxccciternent,anxiety (‘any disturbance of mind’) and eating. Apparently the latter is particularly true in certain parts of E tl=WrlNuEbrb(lnd BKlavdrpl
Press ,980
the United States. It has been suggested that this is due to the habit of drinking iced water and smoking between courses. Heberden also noted that the pain often disappeared on stoppmg the exercise (‘the moment they stand still all this uneasiness vanishes’) and later drew attention to the seriousness of the condition (‘the termination is remarkable. the patients all suddenly fall down. anti perish almost immediately’). This is a classic description of sudden cardiac death (ventricular fibrillation) resulting from an acute myocardial infarction. Our hypothetical research director would then take note of Bum’s finding in 1809 that ‘in dl patients that have died of Syncope Anginosa, the coronary arteries have either been found ossified or cartilaginous’ and would doubtless also take cognizance of the recent ( 1977) survey by Roberts Jnd Spray that ‘all (anginal) patients on necropsy showed a greater than 75% narrowing of the left anterior descending coronary artery by atheromatous plaques and that almost all (96% and 78% respectively) have a similar severe narrowing of the right wronary artery and of the left circumflex branch’. He would however also discover (mainly from the extensive studies of Maseri’s group in Pisa and now in London) that there are really two kinds of angina: the majority have a reduced coronary artery lumen due to atheroma but a significant number (perhaps IO-20% of all angina1 patients) have typical chest pain but essentially normal coronary arteries. His conclusion might w~ellbe that this form of angina, due to coronary vasospasm, might be amenable to coronary vasodilator drugs (as was outlined in a recent issue of TIPS by Imai’) but that ‘c\assicat’ angina ,would not be improved by drugs with a predominant dilator action on coronary arterioles. He might, I think correctly, surmise that if there were a major obstruction in the main supplying vessels, the heart would respond by dilatation of the resistance vessels (the
arterioles) distal to the obstruction and that to design drugs with a predominant action at this particular site within the coronary circulation might not be especially helpful. I think that it is at this point that our research director might. quite legitimately, decide that there was very little future in the exercise and switch his attention to ‘designing’ yet another @adrenoceptor blocking agent. If he persevered however. he would discover that another approach to the problem was open to him. This would depend upon his understanding of the haemodynamic responses preceding anginal pain. If he did he would have learnt a most important lesson. namely that a clear understanding of the pathophysiology of a disease state is fundamental to any attempt to design drugs for that condition. Angina is really a form of acute, reversible. ventricular failure. This has been detailed demonstrated by clearly haemodynamic investigations in patients subjected either to exercise (treadmill or bicycle ergometer) or to electrical intracardiac pacing such that the heart rate is increased to levels similar to those observed in exercise. If the lumen of the left ventricle is also catheterized. and pressure recorded, it can be shown that pacing leads to an abnormal increase in left ventricular end-diastolic (filling) pressure (LVEDP) and this is also reflected in elevated pulmonary artery and pulmonary wedge pressures. LVJZDP can increase to levels as hiih as 40 mmHg in patients with angina; the range for normal subjects during exercise is 8-l 0 mmHg. This abnormal increase in fiiing pressure (and volume) is partly due to a reduced myocardial compliance (or ‘give’). It is not accompanied by a parallel increase in stroke volume, and left ventricular function curves are shifted downwards and to the right. There are two main consequences of this abnormal elevation in filling pressure (Fig. 1). Firstly, there is an increase in myocardial wall tension, that is an increased stretch of the cardiac muscle fibres at rest. This often, although not always, leads to an increase in cardiac size; either way, myocardial orvgep demands would be increased. The other consequence is underpcrfusion of the deeper (endocardial) regions of the ventricular wall, a phenomenon admirabiy described 3s the ‘diastolic crunch’, Fig. 1 shows how this arises and also reveals that there might be three possible pharmacological approaches to alleviating this problem: (1) A crrr&rc s&u&r~ might alleviate the condition and our research director
tnight, againlegitimately. draw the parallel with the stt~t~on in chronic cardiac failure and its alhviation with digitalis glycosidea. He might decide that if he could reduce heart size and myocardial wall tension (important determinants of rarai myocardial oxygen consumption) this decrease in oxygen rsquirements might outweigh an increase demanded by the improved myocardial contractility. (2) A second approach would be to attempt to reduce the gross& elevated ventricular filling pressure by an increnrp in venouf ru~~~ce. lfour director was also a medical historian he would pmbably remember that Lauder Brunton in 1867 drew attention to the fact that angina1 pain could be reduced by bleeding (‘small bleedings of three or four ounces by venesection were alwrjseffective’). The obvious way to achieve this by pharmacological means would be to search for dilator drugs which were more effective on venous smooth rmtscle than elsewhere within the peripheral vascular bed. One way that this could be examined would be to set up isolated preparations of the circufarly arranged smooth muscle from ~~~~ral
veins and artcries Our now mcreasingl) aware director would discover. perhaps to his surprise. that wrne dilator {and constrictor) drugs dkz indeed have an almost selective effect on venous as opposed to arterial or, more important. arteriolar smooth muscle’. The administration of such a compound would prevent the nbnormal increase in left ventricular filling pressure and end-diastolic volume observed in angina1 patients on exertion; chest pain would thus be relieved because of the reduced myocardial oxygen demarids and the removal of the ‘diastolic crunch’. Although to produce a drug possessing both These particular pharmacological properties would be a major advance our ‘ideal director’ might feel he could gild his golden drug wtth another precious layer of pharmacological activity. Looking again at Fig. I he might decide that it would probably be useful if his drug possessed: (3) the capacity to ddate the large intramural arteries running at right angles through the ventricular wall from the major supplying epicardial vessels to the su~nd~ard~l plexus. This woutd be a
‘selective’ effect on the larger coronar) vessels 9s opposed to a general corf3nary (arteriofar) vasodiiator action. it could bc argued that such an effect would result ii increased endocardial perfusion and an increase in the rndolepi blood flop ratio. Such a dw would have the added advantage of being suitable for the treatment of variant angina since it would al%, relieve large coronary artery spasm. There are other properties that could be buiIt into our ‘ideal’ antianginal drug. It could be cirgued for example that to interfere with the perception of pain at the level of the central nervous system might be beneficial and that if the individual anginai patient was unfortunate enough (many do) to develop a? some time an acute myocardial infarction. an antidysrh! thmic action and an abil$ to reduce the area of ischaemic damage might alscr be helpful. The board of management to ahorn our hypothetical research director was responsible might be forgiven for belicring that such a dmg could not be designed or produced. Of course. with existing techniques for screening and discovering prospective antianginal agents. the) Hould probabl) be
Diastolic pmsaum 80 mmHg \
Lumen
obstrucrea
athemmatouo
by
Prawn2
Oiiolic pressuredistal
\
;* SLbendclcardiil Parfuslon Pressufe =80-5=
75mmHg
During
angina LMDP
SEDP
=&l-30
= 30 mmng
: lOmmt(g
to
7YP.S-November
430 right. However the almost unbelievable fact is that such a drug actually exists and indeed has been used successfully in the therapy of angina for a hundred ~SUS. Nitroglycerin really is a most remarkable drug. It was discovered, you will observe, not through the chemical tinkerings of an existing active nucleus. or through an examin+ tion of that ‘basic law’ of drug development the ‘structure-activity relationship’ (nor even through application of the Hansch analysis) but through the stroke of genius of a busy physician with a clear and basic understanding of circulatory physiology. William Murrell, when he surmised in 1879. that, ‘from a consideration of the physiclogical [we would today say pharmacological] action of the drug it would probilbly be of value in the treatment of angina”. probably laid claims to be the first clinical pharmacologist. James Black. many years later. wrote in similar vein about the idea that fiblocking drugs might
be valuable in the treatment of the same pathological condition. I wonder whether perhaps he had studied Murrell’s original Lancer paper. What Murrell unfortunately did not foresee was that his drug might also be useful in another condition, one from which he himself died in June 1’912. For the latest saga in the history of this remarkable ‘centenarian’ is that, as with other peripheral vasodilators. nitroglycerin is also of value in decreasing pre (and after) load in congestive heart failure’. I salute- a truly remarkable drug.
Readlhlgllst 1
1.07439 (I 977) Sr. 1.
Imai, S. ( 1979) 7iend~ fharmac01. Sri.
2 Mackenlie. J. II. and Parratt, J. R. PharmuvI. ho. 1M-1 60 3 Murrell.W.(1679)1~nc~ri.81~1 4 Parrart. J. R. k.1979) 1. Phwm. 801409
Phamcol.
3 I.
Wndina enerav alpdthe excitatjon of~ormone receptors _
_
T. J. Franklin Depwmenr of Siochemistq~, ICI L Id.. Mvrside. Aide&y
The 1970s saw an enormously increased interest in the biochemistry of hormone receptors. The availability of many radiolabelled drugs and hormones made receptor binding studies one of the more popular and fruitful activities in biochemical pharmacology. Receptor: whose excitation is closely olupled to an easily measured bitixhemical response, such as increased cyclic AMP synthesis, are especially attractive objects of study because the action of hormones and synthetic analogues on the biochemical responses can be usefully compared with the results of the receptor binding studies. A fascinating and complex picture has emerged of the biochemical mechanisms which couple the excitation of certain receptors to the stimulation of r;denylate cyclase’. Whilst progress in elucidating the biti hemical evems associated with the excitation of otber types of receptors has been less exhilarating, there is no doubt that receptor excitation is a remarkably effective trigger that initiates the biochemical changes which result in the characteristq.c biological response. C EbcvrrlSmbIfdhd BiancdiralPree I 9811
I980
Park. ~ia.cch*s~e~d.Cbeshire SKI0 4TG. U.K.
in complete contrast we know little 0:’ nothing about the molecular mechanisms of receptor excitation itself or of the details of the interactions between hormones anrl their receptors. How do agonists excicc their receptors? What is the molecular basis for the e:Eficacy of partial agonist!? Why are some competitive antagonists of hormones enti;ely without agonist activity? Pharmacologists have puzzled over these questions for decades and precise answers znwit the elucidation of the molecular anatomy of receptors, their specialized m&environments and the conformatiohai structures of excitatory and inhibitory ligands as they bind to their receptors. In the meantime we can speculate in the hope that our !;peculations suggest experiments that may help towards understanding. A major hindrance to scientific progress in the late twentieth century is the compartmentation of ideas that results from extreme specialization. For example, investigators of receptor pharmacology do not, in general, spend much time with enzymologistsconcerned with the mechan-
isms of enzyme catalysis. In an attempt at bridge building, I hope to show in this commentary that one of the ;nost important current concepts in molecular enzymology may have major implication for our eventual understanding of th,* nature of the efficacy of agonis.,, BIIing energy and enzyme catalysis A few years ago in a classic review, W. P. JencksZ analysed the contribution of the intru,ric free binding energy, AGIS.L. released when a substrate binds to the active site of an enzyme, to the efficiency of the catalytic process. He noted that the Michaelis constants, Km, of many very specific substrates are remarkably high, i.e. between 0.1 and 0.01 mM. If the Km value measures the affinity of a substrate for its enzyme. such values suggest relatively weak binding, a conclusion apparently at odds with the exquisite specificity of many interactions. Jencks enzyme-substrate resolved this contradiction by proposing that part of the intrinsic free energy of binding is used to ‘pay’ for the efficiency of catalysis. Transition state theory holds that enzymic catalysis depends essentially upon the ability of enzymes to lower the free energy of activation to achieve the transition state intermediate (Fig. 1). In the absence of the specific enzyme, a reaction such as: A+(B)
+c
where (B) is the transition state intermediate between the substrate, A, and the product, C, will be very slow if the energy bar-