MEETING BRIEFS FROM ATLANTA
New candidates for treating Alzheimer's Two new compounds, designated HP 290 and HP 749, have been shown in animal studies to hold promise for enhancing brain function and reversing memory deficits associated with Alzheimer's disease, according to scientists from HoechstRoussel Pharmaceuticals, Somerville, N.J. The disease affects some 4 million individuals in the U.S. According to R. Richard L. Hamer, one of the most consistent brain defects in Alz heimer's patients is a deficit of the neurotransmitter acetylcho line. Hamer says HP 290 selectively inhibits the breakdown of acetylcholine in the brain, but does not exhibit many of the negative side effects associated with previous drugs that also blocked acetylcholine breakdown. The drug "is active in re versing memory deficits in animal models" of Alzheimer's dis ease, Hamer says, and should enter clinical trials shortly. Jo seph T. Klein calls HP 749 a "promising second-generation drug for the treatment of Alzheimer's disease." In addition to an acetylcholine deficiency, Alzheimer's patients also suffer from a lack of norepinephrine, another central nervous system neurotransmitter. In fact, Klein says, some studies suggest that correction of the norepinephrine deficiency may be required before enhanced performance resulting from the correction of the acetylcholine deficiency can be observed. HP 749 appears to enhance both neurotransmitters. Klein also points out that depression is commonly associated with Alzheimer's disease, and that many antidepressants that enhance norepinephrine also frequently antagonize acetylcholine. HP 749 appears to have both an antidepressant activity and the ability to enhance acetylcholine. The drug is now in Phase I clinical trials. Chronic cocaine use depletes dopamine Research at Emory University, Atlanta, appears to confirm what has been suspected for some time—that chronic use of cocaine results in a significant depletion of the neurotransmit ter dopamine in certain areas of the brain. Joseph B. Justice Jr., a chemistry professor at Emory, says it has been known that cocaine overstimulates dopaminergic neurons by blocking the reuptake of dopamine by the neurons that release it. One hypothesis is that the intense craving habitual cocaine users experience after withdrawal of the drug is caused by a defi ciency of dopamine. The notion is that the brain of a cocaine user responds to the apparent chronic excess of dopamine by producing less of the neurotransmitter. Justice and coworkers implant a guide channel into a region of interest in a rat's brain, and after the animal recovers from the surgery, they expose it to a moderate, daily dose of cocaine for 10 days. They insert into the channel a small sampler (2 mm long and 100 μητι in diameter) made of a semipermeable membrane that excludes molecules with molecular weights greater than about 5000. This prevents enzymes that might degrade dopamine from be ing sampled. The sampler enables the chemists to withdraw amounts of extracellular fluid for analysis. They find dopamine is not depressed in the rat's brain for the first several days of 28
April 29, 1991 C&EN
the experiment, but after 10 days of exposure to cocaine, dopamine levels are depressed and remain so for several days after the treatment with cocaine stops. Unusual modification of a nucleoside The relatively unusual nucleoside, 4'-azidothymidine, is a po tent in-vitro inhibitor of human immunodeficiency virus (HIV), which is the cause of AIDS, according to scientists at Syntex Research, Palo Alto, Calif. Syntex scientist Ernest J. Prisbe says modification of the 4'-position of nucleosides has rarely been reported. However, modified nucleosides have achieved prominence in recent years as anti-HIV agents, stimulating Prisbe and coworkers Hans Maag and Julien P. H. Verheyden to investigate a series of 4'-modified compounds. (AZT, the only compound currently approved for treating HIV infections is 2',3'-dideoxy-3'-azidothymidine; other promising anti-HIV nu cleoside analogs are also modified at the 3'-position.) The sci entists achieved the synthesis of 4'-azidothymidine as well as of 4'-azido-3'-deoxythymidine. The latter compound exhibited no anti-HIV activity, Prisbe says, while 4,-azidothymidine was comparable with AZT in assays of anti-HIV activity. Stable, water-soluble semiconducting resins made Air-stable, water-soluble polyacetylene resins with doped elec trical conductivities of 10"2 Siemens per cm were described by chemists from the University of Lowell, Mass. Though conduc tivities are still low, such stability and solubility may someday permit fabrication of the material into useful devices. Polymer chemistry professor Alexandre Blumstein detailed polymeriza tion with quaternerization of 4-ethynylpyridine by reaction with dodecyl bromide and of di-4-pyridinylacetylene with dodecyl bromide or heptyl methanesulfonate. Polymer chains had pen dant alkylpyridinium groups, and ultraviolet spectra indicated 10 to 20 conjugated double bonds. Postdoctoral fellow Sundar Subramanyam told of doping cast films with tetrathiafulvalene. Their collaborators were electrical engineering professor Sam son Mil'shtein and graduate student M. S. Chetan. Cross-reactivity of drug analogs predicted Molecular modeling can be used to predict cross-reactivity in a series of drug analogs, say David A. Nugiel of Du Pont Merck Pharmaceuticals and Lawrence R. Soma and Linda Keller of the School of Veterinary Medicine of the University of Pennsyl vania. The researchers use molecular modeling techniques to compare the structures of fentanyl derivatives and predict the potential for cross-reactivity of each structure with fentanyl monoclonal antibodies. Although monoclonals are highly spe cific, some cross-reactivity can occur with molecules that are closely related structurally. "Cross-reactivity is probably related to the molecule's orientation with the antibody combining site," says Nugiel. "This hypothesis was tested using molecular mod eling technology." Fentanyl monoclonals were produced by in-
MEETING BRIEFS FROM ATLANTA
oculating mice with a conjugate of fentanyl and bovine serum albumin. Then, eight fentanyl analogs were constructed with molecular modeling software and superimposed on the parent structure. Three fentanyl derivatives that cross-react with the monoclonals were found to overlap almost identically with fen tanyl. Five other fentanyl analogs that did not cross-react were found to have 3-D orientations different from fentanyl. This technique for predicting cross-reactivity, says Nugiel, "may have broad applications in other molecular and biopharmaceutical systems." Method makes cyclic ethers Treatment of alcohols or diols with silver acetate and bromine in pentane yields five-membered cyclic ethers by abstraction of the δ-hydrogen, according to graduate student Ling Yang of American University, Washington, D.C. The cyclic and spiro ethers and spiroketals products are important structural ele ments in such biologically active natural products as pheromones. Working with organic chemistry professor Nina M. Röscher, Yang converted 1-methyl-1-cycloheptanol to 1-methyl8-oxabicyclo[3.2.1]octane, 1-methyl-1-cyclooctanol to 1-methyl-9-oxabicyclo[4.2.1]nonane, 3,7-dimethyl-1,7-octanediol to 2,2,9-trimethyl-1,6-dioxaspiro[4.4]nonane, and 2,5-hexanediol to 1,4-dimethyl-5,6-dioxabicyclo[2.1.1]hexane. Cellulose produced in vitro Chemistry professor Shiro Kobayashi of Tohoku University, Sendai, Japan, has claimed the first in-vitro synthesis of cellulose. This achievement may lead to general methods to make many high molecular weight polysaccharides of biological and industrial importance. Working with Shin-ichiro Shoda and Keita Kashiwa, Kobayashi stirred ß-D-cellobiosyl fluoride and cellulase in a 5:1 mixture of acetonitrile and aqueous buffer at 30 °C for 12 hours to get a 5 4 % yield of water-insoluble polymer 22 glucose units long and 10% of water-soluble cellohexose. Nuclear magnetic resonance, x-ray diffraction, and infrared studies indicated the water-insoluble polymer was identical with natural cellulose but more crystalline. Polyvinylbenzophenone indicates solvent dryness Benzoylation of polystyrene gives a noncontaminating indicator of solvent dryness, says chemistry professor Craig A. Ogle of the University of North Carolina, Charlotte. Benzophenone is used as an indicator in drying of ethereal solvents over sodium or potassium by the intense blue color of its radical anion. But codistillation of benzophenone and benzhydrol with dried solvent can give spectroscopic interferences in studies of alkyllithiums and carbanions in such solvents. Working with Bronco Gordon of PCI, University Park, Pa., Ogle reacted either polystyrene of molecular weight 45,000 or polystyrene beads crosslinked with 2 % divinylbenzene with benzoyl chloride and aluminum chloride in carbon disulfide to get 20, 50, or 6 8 %
benzoylation. Ultraviolet spectra of tetrahydrofuran distilled from polymer plus alkali metal showed no absorbances above 220 nm. Use of benzoylated beads rather than soluble resin allowed easier cleaning of the still pot afterward. Nonpyrophoric methyllithium developed Methyllithium (1.6M) in cumene solution is a nonpyrophoric product for industrial synthesis, according to chemist Robert C. Morrison of FMC Corp.'s lithium division, Bessemer City, N.C. The solution avoids use of highly flammable diethyl ether solvent and might find favor in large-scale production of drugs, pesticides, pheromones, and flavor, fragrance, and research compounds. He described making it from lithium and methyl chloride in cumene that was also 1.8 to 2.3M in tetrahydrofuran. In-situ generation of 7 mole-% dimethylmagnesium furnished a stabilizer. The company will sell the product at about $90 per lb of methyllithium contained. Researchers study ring around the collar A new study indicates that polyester/cotton clothing left unlaundered for a week or more can become permanently discolored from skin oil reactions that occur over time. The study, by S. Kay Obendorf and Eun Kyung Park of the department of textiles and apparel at Cornell University, focused on the chemical changes that take place in body oils on clothing and the effects of these changes on soil removal. The researchers found the carbon-carbon double bonds of unsaturated oils in sebum from the skin (oleic acid, triolein, and squalene) oxidize with time and become more polar. "It was startling to us to find that oil compounds became more polar and therefore more easily removable when they aged," says Obendorf. "But at the same time there are other things happening that make soil removal more difficult." Namely, oxidation of the oils over time causes formation of polymers and yellow oxidation products that are difficult to extract with detergents. The study could lead to improved laundry products, the researchers say. "Hedge" aids chemical safety database searching Use of a "hedge" can make it easier to locate chemical safety data from on-line sources, according to information analyst Jerry L. Curnutt of Dow Chemical. A concept developed by the National Library of Medicine, a hedge is a search tool that includes numerous specific search terms related by concept. This makes it possible to retrieve information containing many spelling variations and synonyms. Curnutt arranged reactivechemical search terms into eight categories and developed an initial hedge containing more than 100 search terms. Eliminating some terms and simplifying search phrases resulted in a hedge that searches chemical safety databases very efficiently. In addition, the hedge made it possible for Curnutt to develop a reactive chemical value index, which ranks databases according to their chemical safety content. April 29, 1991 C&EN 29
