chemicals, as well as their lipophilic/ hydrophilic balance. Unlike the Hansch route, however, which depends on statistical, computerized methodology based on equations derived from regression analyses, Topliss' method is more qualitative and avoids the use of computers. "Many organic chemists aren't very comfortable with or interested in mathematical approaches of the kind proposed by Hansch," Topliss argues. Too, the biological data often cannot be expressed in precise quantitative terms, he adds. Using the Topliss method, some four or five compound variations are considered in the initial screening in place of the six to 12 needed for a regression analysis. By drawing up a simple ranking system, it's possible to determine approximate parameter dependencies and to select which of the parameters are controlling or influencing the molecules' biological activity, Topliss explains. The "manual Hansch approach," as Topliss dubs his method, can be useful in evaluating a batch of chemical derivatives. There is no special commitment to resources over and above the ordinary. "It helps in that phase of a particular drug design problem where one has a lead and one seeks to identify compounds having higher potency or a higher therapeutic index," he maintains. Much depends, of course, on being able to identify such a "lead" chemical in the first place. As Arthur Patchett observes, "New lead discovery [still] is an art rather than a science." However, Ariens is optimistic about the increased chances of finding such lead chemicals. "The continuing development of improved research tools that can isolate and identify molecules in biological systems at extremely low concentrations is helping point the way to our understanding of physiological processes at the molecular level," he notes. "Once you have a sound lead, then you have a good rationale to come up with a reasonably active compound." Dermot A. O'Sullivan, C&EN London
Tripeptide analogs trip hormone action During the six years or so since the chemical nature of thyrotropin-releasing hormone (TRH) was determined, the hormone has been the focal point of considerable research effort. One direction that this research has taken has centered on synthesizing analogs of the tripeptide. Three such analogs now have been made that enhance the effect the molecule has on the central nervous system while leaving the thyrotropin-releasing influence essentially unchanged, according to Dr. Robert F. Hirschmann of Merck Sharp & Dohme's research laboratories. TRH is one of a number of peptides produced by the hypothalamus. These in turn stimulate or inhibit release of regulatory hormones from the neighboring pituitary gland at the base of the brain.
TRH, for instance, triggers release of thyrotropin, the thyroid-stimulating hormone. However, TRH has since been shown to have a second action. It has a generally enhancing effect on motor activity in certain situations. The three analogs that Hirschmann described at the Fifth International Symposium on Medicinal Chemistry in Paris last month markedly increase the central nervous system influence over the other. Native TRH consists of pyroglutamic acid, histidine, and proline amide linked together in that order (C&EN, Dec. 14, 1970, page 39). Hirschmann's associates, Dr. Frederick W. Holly, Dr. Daniel F. Veber, and their colleagues, made a series of analogs in which homopyroglutamic acid replaces the pyroglutamic moiety, and thioproline amide replaces the proline amide. In biological tests conducted by Dr. Victor Litti and Dr. Curt Porter, the
central nervous system activity of the analog containing thioproline amide is two to three times that of TRH, and the hormonal effect is lower. In the analog containing homopyroglutamic acid, there is a fourfold increase in the effect on the central nervous system but no change in hormonal action. The most striking difference in hormonal activity results when both the pyroglutamic acid and proline amide are replaced. In this TRH analog, containing homopyroglutamic acid and thioproline amide, the influence on the central nervous system is 15 times that of TRH. There is no marked difference in the hormone-stimulating function compared with TRH. These results, Hirschmann reasons, support earlier findings that effects on the central nervous system can be observed in animals from which the pituitary glands have been removed. D
Technology Sites sought for nuclear waste disposal Sometime in the mid-1980's most of the world's nuclear nations will begin reprocessing nuclear fuel on a large scale. Reprocessing will increase the overall efficiency of nuclear power generation, initiate a new industry, and prolong the useful life of nuclear fuel resources. It also will signal an abrupt increase in the amount of high-level radioactive waste that must safely be disposed of. The International Symposium on the Management of Wastes from the LWR (lightwater reactor) Fuel Cycle, held last month in Denver, provided a good vantage point for surveying the different national approaches to that disposal. About 10 years of development time remain for providing a disposal system for which the general approach has been all but decided—namely, deep burial in stable rock formations. The technology for burial has been devised and isn't expected to present any insurmountable problems. The main problem is that of finding the spots to bury the waste. Most nuclear nations are converging on suitable sites. Some of them are engaging in cooperative action for common burial places. And the necessarily unknown stability of rock formations over hundreds of thousands of years has become somewhat less of an unknown with discovery in 1972 of a "natural reactor" in Gabon. The Belgians have been pressing forward with nuclear waste disposal systems since at least 1974, when it was decided to build a pilot disposal facility near Mol. Though initially intended for the storage of intermediate-level and alpha-bearing wastes, the site at Mol also will be evaluated concurrently for the storage of high-level wastes. If no problems develop, an underground cavity of about 10,000 cu m will be mined at depths greater than 200 m. This cavity is scheduled to be ready by 1979.
French policies on waste disposal still are evolving. One particular issue, not yet resolved, is whether to separate fission products from actinides. Whatever is finally decided, there seems little doubt that the French will bury their wastes in deep formations of rock salt or crystalline rocks. The target year for the first repository is 1985 but the actual site has not been chosen. Most of the talk in Denver about a French site suggested that an area near La Hague may be chosen. The very dense granite under La Hague may be nearly ideal from the standpoint of low porosity, but some doubts remain about the nature of the underground water flows in the area. In Italy, results of tests in impervious clay deposits at Basilicata near Taranto are promising. Some salt domes, if they prove extensive enough, also may be tested before the deadline for a processing pilot plant in the mid-1980's. The first Spanish reprocessing plant is scheduled for the late 1980's and the hope is that the first waste depository will be ready by 1990. Since some low-level wastes currently are being stored in abandoned uranium mines in the Sierra Albarrana, there is reason to believe that the mines may be employed for future storage of high-level wastes. The Spaniards also are examining salt domes and several anhydrite deposits. So far, no selection has been made. The most likely possibility in Sweden is burial in bedrock; there seems to be little alternative, even though most of the exploration conducted so far has indicated that subsurface water migration will be a major problem. With this in mind, the Swedes have been developing new techniques for cementing bedrock formations against water intrusion. This promising idea may be the only way to provide stable burial sites in Sweden. Aug. 9, 1976 C&EN
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