Black and Beta-Blockers
The introduction of beta-blockers is widely considered one of the most revolutionary, conceptually, in our quest to conquer human ailments. The approach of rational drug design also revolutionized how drugs are discovered.
Adrenaline (epinephrine) and noradrenaline (norepinephrine) are secreted by the adrenal gland. These hormones bind to their corresponding receptors and elicit biological responses. Stimulation of the sympathetic nervous system due to fright leads to preparation of the system tor fight or flight. Increase of adrenaline results in dilation of bronchi, dilation of pupils, constriction of peripheral (outside the central nervous system) blood vessels, and so forth. The cardiotoxic effects of catecholamines were determined in late 1940s and early 1950s. As a consequence, an excess of adrenaline can cause heart attack and hypertension.
Adrenaline and noradrenaline stimulate adrenergic receptors. As early as 1948, Raymond P. Ahlquist at the Medical College of Georgia speculated that there were two types of adrenergic receptors (adrenoceptors for short), which he termed alpha-adrenoceptor and beta-adrenoceptor—later further subdivided as beta-1 and beta-2. The beta-adrenoceptors belong to a family of G-protein-coupled receptors (GPCRs). G-proteins, in turn, are guanine nucleotide-binding regulatory proteins.
Because Ahlquist’s theory was so revolutionary at the time, he found himself having difficulty publishing his carefully reasoned and thoroughly researched paper. He later commented: «The original paper was rejected by the. Journal of Pharmacology and Experimental Therapeutics, was a loser in the Abel Award competition and finally was published in the American Journal of Physiology due to my personal friendship with a great physiologist, W. F. Hamilton.»
Ahlquist’s hypothesis was largely ignored for the first 10 years after its publication. In 1958, С. E. Powell and I. H. Slater of the Eli Lilly Company were searching for a long-acting and specific bronchodilator to compete with isoprenaline. They prepared DCI (the dichloro analog of isoprenaline) and demonstrated that it inhibited the relaxation of bronchial smooth muscle elicited by isoprenaline and also the cardiac actions of isoprenaline. As an added bonus, DCI was found to be the first beta-adrenoreceptor blocking reagent, also known as beta-blocker. The finding that DCI selectively blocked beta-receptors has proven to be a significant advance in human pharmacotherapy.
James W. Black was born on June 14,1924, in Scotland. In 1958, Imperial Chemical Industries (ICI) hired him from the Physiology Department at Glasgow University as a senior pharmacologist, although he had had no previous training in pharmacology. Black started to look for an antianginal agent that would reduce sympathetic stimulation of the heart and thereby decrease myocardial oxygen demand. To do this he applied his knowledge of how chemical messengers such as adrenaline and noradrenaline bind to the two major types of cell receptors in the organs of the body: alpha-adrenoceptors and beta-adrenoceptors. He spent a decade attempting to understand how cells talk to each other chemically. Black and colleagues investigated how these messengers and receptors might be manipulated to produce a desired medical result. He looked into the pharmacological properties of DCI, which not only possessed all the characteristics of a beta-blocker but also had a marked stimulant effect on the heart, an intrinsic sympathomimetic action (ISA). This led, in time, to the development of what came to be known as beta-blockers—substances that beat adrenaline to its target and, by acting as false messengers, bring about the intended pharmacological effect.
Beta-blockers interfere with the body’s release of adrenaline. They are false messengers that infiltrate the messenger/receptor mechanism in human cells that trigger the release of adrenaline, thus calming the hearts of people who suffer from high blood pressure or tachycardia. In other words, beta-blockers act primarily by blocking the stimulation of the beta-receptors—the nerve endings that affect heart rate and the force of contraction. Their actions cause a decrease in the amount of blood pumped by the heart and thus lead to the lowering of blood pressure.
In 1962, Black and his colleagues succeeded in making a beta-blocker that was devoid of the stimulant effect on the heart: pronethalol. Unfortunately, pronethalol was withdrawn from further development when it was found to cause thymic tumors in mice. ICI eventually produced the drug propranolol (trade name Inderal), which possessed a better efficacy and safety profile. Not only was propranolol more potent than pronethalol, but it was also devoid of the carcinogenic properties in mice. Propranolol is now widely used in the management of angina, hypertension, arrhythmia, and migraine headaches. Two additional beta-blockers, atenolol (trade name Tenormin) and practolol (trade name Dalzic), were later discovered and marketed by ICI. Beta-blockers were not just a new class of drugs; they represented a revolutionary approach to pharmaceutical research. Black changed the process of drug discovery from one of hunting to one of engineering—employing rational drug design to discover novel compounds that nature had not thought of. In 1963, Black moved to Smith-Kline French, a small and little-known drug outfit. From 1963 to 1972, he developed the drug cimetidine (Tagamet), which decreases the secretion of acid in the stomach, thereby promoting the healing of peptic ulcers. Tagamet was the first blockbuster drug in pharmaceutical history—it generated more than $i billion per year in sales and transformed SmithKline French into one of the biggest pharmaceutical companies in the world.
Never a content soul, in 1972 Black took the prestigious position of Professor of Pharmacology at University Hospital, King’s College. He was awarded the Nobel Prize in Physiology or Medicine in 1988, along with Gertrude (Trudy) Elion and George Hitchings, both from Glaxo-Wellcome Pharmaceuticals, for their discoveries of important principles for drug treatment.
Beta-blockers have made a major impact on the treatment of cardiovascular diseases since their discovery. Almost every single major pharmaceutical company was involved with beta-blockers. About 2,000 patents have been filed, and approximately 20 major drugs are marketed as beta-blockers. ICI alone tallied three major beta-blockers: propranolol, atenolol, and practolol. In addition, there are Hassle’s alprenolol, Astra’s metopro-lol, Sandoz’s pindolol, Ciba’s oxprenolol, May and Baker’s acebutolol, Synthelabo-Searle’s betaxolol, and many more.
In addition to their primary uses in treating hypertension and cardiac impairments, beta-blockers have also been used in anesthesia to control a racing or irregular heart. Some beta-blockers even possess interesting central nervous system effects. Propranolol, for instance, causes the brain to enhance the memory of emotionally charged events, which would otherwise have been suppressed. Propranolol has been reputed to erase painful memories as well—a magic potion indeed. Somehow, propranolol also enables the person taking it to look back at stressful past events in a calm manner.
Beta-blockers are frequently used by performing artists and athletes to reduce anxiety. Because anxiety is associated with increased activity of the sympathetic nervous system and increased levels of catecholamines, beta-blockers have been proven to be effective in lowering anxiety levels. It may be, in part, that the sensation of the racing heart causes the person to feel or at least to be aware of his or her anxiety and that blocking one symptom ameliorates the other. Whereas performing artists may take beta-blockers to reduce stage fright, it is illegal for athletes to take them during competitions. In 1986, the National Collegiate Athletic Association (NCAA) listed beta-blockers as prohibited performance-enhancing drugs. The use of beta-blockers is prohibited in marksmanship, archery, ski jumping, freestyle skiing, sailing, synchronized swimming, diving, and pentathlon in the Olympics. The International Olympic Committee (IOC) considers the use of adrenergic antagonists, including alpha- and beta-blockers, a serious offense and rarely accepts any excuses.
In their quest for beta-blockers, medicinal chemists prepared more than 100,000 compounds. The pharmaceutical industry would not be what it is today without beta-blockers, the knowledge and profit gained catapulted the industry to a new height.
