The significance of the group's findings, Heicklen says, is that the chlorofluoromethanes are removed very efficiently to produce CI or CIO both by photodissociation and by 0 attack. In fact, he says, the rates of these processes are as fast as theoretically possible. Thus, the molecules are indeed a threat to the ozone layer. Dr. Harold S. Johnston of the University of California, Berkeley, says that more has been learned about the stratosphere in the past three years than was ever known before. He cites a three-year, $50 million study made by the Department of Transportation through its Climatic Impact Assessment Program. That program included research on the stratosphere, stratospheric ozone, and the vulnerability of stratospheric ozone to future fleets of supersonic transports (C&EN, Jan. 27, page 8). The new data from the DOT study, Johnston says, are directly applicable to the chlorofluorocarbon problem. Johnston draws a direct parallel between the now well-understood role of natural stratospheric nitrogen oxides and the problem of stratospheric pollution by chlorofluorocarbons. Nitrous oxide is released from the
NRC picks panel members for study of stratosphere Chairman, Dr. H. S. Gutowsky, director, school of chemical sciences, University of Illinois, Urbana Dr. Julius Chang, University of California, Lawrence Livermore Laboratory Dr. Robert Dickinson, National Center for Atmospheric Research, Boulder, Colo. Dr. James P. Friend, department of chemistry, Drexel University, Philadelphia Dr. Christian E. Junge, MaxPlanck Institut fur Chemie, Mainz, West Germany Dr. Frederick Kaufman, department of chemistry, University of Pittsburgh Dr. R. A. Marcus, department of chemistry, University of Illinois, Urbana Dr. George Pimentel, department of chemistry, University of California, Berkeley Dean H. I. Schiff, York University, Downsview, Ont. Dr. John H. Seinfeld, division of chemistry and chemical engineering, California Institute of Technology, Pasadena Dr. Brian Thrush, department of chemistry, Cambridge University, England Dr. Cheves Walling, department of chemistry, University of Utah, Salt Lake City
soil by natural processes. Inert in the lower atmosphere, it slowly moves into the stratosphere where it is partially converted to nitric oxide plus nitrogen dioxide (NO x ). The NO x destroys some 70% of the ozone, which is formed from solar radiation and oxygen. The global rate of formation of stratospheric NO x , Johnston notes, has been found to be 1 million tons per year. This rate, he says, constitutes a simple, firm reference point for comparison against possible stratospheric pollutants, including chlorofluorocarbons. Meanwhile, as studies are made and data come in, Rowland proposes pinning down the chlorofluorocarbon question with experiments that could be performed during the next few months. He suggests use of special techniques and equipment to detect the amounts of radioactive chlorine in fresh samples of stratospheric air. The radioactive chlorine is formed in small amounts in the stratosphere when molecules of trace argon are struck by cosmic rays. The radioactive chlorine decomposes quickly with a half-life of less than an hour. But if air samples were analyzed quickly for key compounds in the ozone destruction sequence, the presence of radioactive chlorine in the
compounds would constitute evidence that the ozone-depleting reactions are indeed occurring in the stratosphere. Rowland also proposes as a shortterm solution to the chlorofluoromethanes problem the substitution of FC-22 for FC-12. He notes that FC-22 (CHF2C1) is one of three commercial chlorofluorocarbons containing a C—H bond. Chlorofluorocarbons with this or C = C bonds can react, he says, with OH radicals in the lower atmosphere and be destroyed there, unlike chlorofluoromethanes. Even so, it would be just a shortterm solution. Rowland estimates that about 10% of FC-22 will reach the stratosphere and react there. But since it can release only one chlorine atom per molecule, compared to two for FC-12, the relative atmospheric hazard is half of 10%, or 5%. On this basis, he estimates that FC-22 is 20 times less hazardous than FC-12 per molecule. He notes, however, that considerable uncertainty remains in the calculations and the added safety factor could easily be 10 or 40 rather than 20. He also estimates that the safety factor for FC-21 (CHFCI2) and FC-31 (CH2FC1) should be even higher by another factor of five—that is, 50 to 200. •
Hypertensives work by several mechanisms 169th ACS NATIONAL MEETING The underlying causes of essential hypertension, or high blood pressure, are still largely unknown. But the chemical and physical changes that occur in the body with the onset of hypertension have been observed with some degree of precision. This knowledge has enabled pharmaceutical researchers to synthesize antihypertensive drugs to treat the symptoms of this disease that affects millions of people worldwide. By class, antihypertensive drugs fall roughly into three classes of compounds: adrenoceptor antagonists, peripherally acting compounds, and centrally acting compounds. Adrenoceptor antagonists inhibit the action of noradrenaline, a chemical messenger that carries sympathetic nerve impulses to the various organs of the body—particularly the heart and blood vessels, which play a key role in blood pressure control. Peripherally acting drugs work by increasing the degree of vasodilation—in other words, decrease the degree of blood vessel constriction in the hypertensive patient. Centrally acting antihypertensives, on the other hand, get right to the root of the problem, so to speak. They work on the vasomotor center of the lower brain, the section directly responsible for blood pressure control. Drugs acting by these several mechanisms were discussed at a Medicinal
Chemistry Division symposium on recent advances in antihypertensive therapy. Dr. Richard Clarkson of Imperial Chemical Industries' pharmaceutical division in the U.K. led off the program with a discussion of betaadrenoceptor antagonist compounds that show promise for human use. The initial search for a specific beta-adrenoceptor antagonist, Clarkson says, centered on a means of protecting the myocardium (heart muscle) from sympathetic nerve stimulation that would be useful for treating angina pectoris and for patients recovering from heart attacks. Trials with the early compounds synthesized for this purpose proved successful. But these drugs exhibited antihypertensive activity as well. One drug in particular, propranolol, in 1964 was discovered to have antihypertensive activity. It is now marketed in the U.S. as Inderal by Ayerst under license from ICI. Followup studies with other compounds of the propanolamine class, to which propranolol belongs, showed that antihypertensive activity is typical of the class. The specific mechanism by which the beta-blockers act, according to Clarkson, is still uncertain. But there is speculation that they work by one or a combination of modes. These include reduction of cardiac output; suppression of renin release (a proteolytic enzyme responsible for some forms of hypertension); by direct central effects on the brain area responsible for blood April 21, 1975 C&EN
23
Antihypertensives take many forms Propranolol (Ayerst's Inderal)
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pressure control; and by indirect lowering of peripheral resistance. Characteristic actions of the betablockers, according to Clarkson, look roughly like this: Some 50 to 70% of patients treated respond to therapy; the drugs are not overly potent since they produce only mild lowering of blood pressure; their onset of action is not immediate; they produce good control of blood pressure in both prone and upright positions; and they have few side effects. ICl's contribution to all this is a stillexperimental compound called ICI 66,082, a propanolamine related to propranolol. It's as effective as propranolol in animal studies and apparently more than twice as efficacious in humans, based on the dose needed to achieve the desired effect. Interest in antihypertensives that work by peripheral vasodilation has likewise heightened. Medicinal chemist John E. Francis of Ciba-Geigy's pharmaceutical division in Ardsley, N.Y., explains why. Says Francis, "Behind the exploration of vasodilating antihypertensives is the hope of finding a compound that will be effective against all types of hypertension, whether mild, moderate, or severe, without producing disabling central nervous system side effects." Disabling side effects include drowsiness, which reduces patient acceptance of therapy. Thus, the most effective antihypertensive drug in the world could be available, but if the patient isn't willing to continue taking it, then it isn't of much use. This is an important consideration with any antihypertensive drug, or for that matter, any drug at all. Additionally, the drug should not produce tolerance, since patients may require therapy for years. Vasodilators produce some difficulties of their own. Antihypertensives that relax the blood vessels also increase sodium levels in the blood stream, which can be counterproductive. This effect can be controlled by coadministration of a diuretic, some of which—the thiazides, for example 24
C&EN April 21, 1975
—have antihypertensive action of their own. Right now there are only three antihypertensives on the U.S. market that are vasodilators, and two of these, Diazoxide and sodium nitroprusside, are used only in emergency situations, according to Francis. Only hydralazine, developed by Ciba scientists and introduced in the U.S. in 1953, is used for the treatment of chronic hypertension. Subsequent modifications of hydralazine convinced researchers that two adjacent nitrogens in a six-membered heteroatom ring with an adjacent hydrazino group are essential for activity of hydralazine analogs in humans. Modifications included dihydralazine (Ciba's Nepresol) with two hydrazino groups. Another group of promising vasodilators, Francis says, are the 2-substituted 6,7-dimethoxyquinazolines, of which Pfizer's Prazosin is a member. Research with this group was largely the work of Pfizer scientists and began with modifications of 2-substituted 6,7-dimethoxyquinazolin-4-ones. Scrutiny of more than 50 analogs of this latter group showed that the 2-aminoid group could be varied to some extent without drastically altering activity. But research also demonstrated that the 6,7-dimethoxy substitution is essential for activity. Replacing the methoxyls, reduces or eliminates antihypertensive activity. In animal studies, Prazosin and related compounds have proved to be more potent than hydralazine. Prazosin has been shown to be a potent antihypertensive in clinical trials as well, and it is marketed in several foreign countries. It will be marketed shortly in the U.S. The search for antihypertensives acting by a peripheral mechanism is not limited to these few compound types, Francis notes. Scientists at Smith Kline & French Laboratories in Philadelphia have synthesized a compound with a dihydropyridine nucleus that is potent and long acting in dogs (SK & F
24,260) and resembles a Bayer compound called Nifedipine. And these are just a few examples. Of the centrally acting drugs, clonidine, a substituted imidazoline, appears to be promising. It will be marketed in the U.S. as Catapres by Boehringer Ingelheim, a West German pharmaceutical maker. Originally synthesized as a nasal decongestant, the drug has proved to be an effective means of controlling blood pressure, according to Dr. Wolfgang Hoefke, a Boehringer pharmacologist. This compound works by central alpha-adrenoceptor stimulation, as opposed to peripheral adrenoceptor antagonism. Modifications of the phenyl-imino-imidazolines show that chloro substitution in the 2 and 6 positions produces the maximum antihypertensive effect. Replacing the chloro substitutes with either bromine or trifluoromethyl groups decreases activity, Hoefke says, and moving the chlorines to other positions on the phenyl ring likewise decreases activity. Extending the bridge between the phenyl ring and the imidazoline ring, and expansion to a six-, seven-, or eight-membered ring also decreases activity. Thus, clonidine, since it was easily the best of the field, was selected to go to market, and it made its debut in the U.S. in 1974. a
Firefly enzyme study uses affinity label
I
169th ACS NATIONAL MEETING
One of the most common methods for studying amino acids at an enzyme's active site involves using an affinity label—a molecule that resembles the normal substrate and has a chemically reactive group, generally an alkylating agent, which reacts with the enzyme and modifies it. Continued on page 27
