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n e w s of t h e w e e k ly than morphine. In animal studies, the compound—ABT-594—doesn't cause withdrawal symptoms like opiates. Unlike morphine, ABT-594 acts through nicotine receptors in nerves rather than opioid receptors [Science, 279, 77 (1998)]. The feat is exciting, says Christopher M. Flores, assistant professor of endodontics and pharmacology at the University of Texas Health Science Center, San Antonio. "ABT-594 represents a new class of analgesic compounds that are nonopioid in nature, raising the possibility of discovering drugs that lack morphine's adverse side effects." ABT-594 resembles the alkaloid epibatidine that National Institutes of Health scientist John W. Daly isolated in 1976 from the skin of an Ecuadorian frog. A potent analgesic in animals, epibatidine's side effects preclude its use in humans. "Abbott has done a fantastic job" in developing a variant with the potential to be clinically useful, Daly says. Both ABT-594 and epibatidine have similar affinities for a nicotine receptor subtype that predominates in the central nervous system. But ABT-594 is 4,000 times less efficient than epibatidine in binding to nicotine receptors at the neuromuscular junction. That explains why the Abbott compound doesn't have epibatidine's adverse neuromuscular side effects, such as paralysis. In various experiments, the Abbott research team showed that ABT-594 modulates pain via pathways in the brain and spinal cord as well as at the peripheral end of pain-sensing nerves. "I think that's one of the reasons ABT594 is such a good [painkilling] agent," says Abbott neuropharmacologist Stephen P. Arneric. "It works at multiple sites." Other pain researchers are cautiously optimistic. "The [Abbott] research is definitely worth following up on, but there's lots more to do," says Allan I. Basbaum, chairman of the anatomy department at the University of California, San Francisco. Arneric agrees. "People have been working on opioids for the past several decades, whereas the work on ABT-594 represents basically two years of research," he points out. "So many questions have not yet been answered." One of these questions is whether the compound could evoke a nicotine-like dependency. Flores notes, however, that an ABT-594 variant that would selectively target pain-sensing sites in the periphery "would get around the issue of de16 JANUARY 12, 1998 C&EN
rate of petroleum formation depends critically on the concentration of sulfur radicals formed during the early stages of thermal maturation. He suggests that early petroleum generation from sulfur-rich kerogens results from enhanced rates of Epibatidine Nicotine C-C bond cleavage due to an abundance of sulfur radicals that may initiate freeradical cracking. Lewan's hypothesis is based on pyrolI N^^CI ysis experiments on 1-phenyldodecane (PDD) containing varying concentrations ABT-594 of diethyldisulfide (DEDS). "PDD is commonly used as a model compound for pendence, a phenomenon largely medi- coal and kerogen, and DEDS is a good source of sulfur radicals like those found ated in the brain." There are other hurdles. Getting the in kerogen," he tells C&EN. The experiFood & Drug Administration to approve ments were carried out in isothermal an analgesic drug is extraordinarily dif- closed-system reactors with and without ficult, says Tony L. Yaksh, vice chair- water at temperatures up to 365 °C over man for research in the department of hours to several days. anesthesiology at the University of CaliThe results show that PDD degradafornia, San Diego. "The drug must have tion increases with increasing amounts the ability to alter pain in a way other of DEDS. "My findings provide petrodrugs cannot." leum geochemists with a first approximaBut Yaksh sees a bright side. "Wheth- tion of the kinetic parameters for petroer or not ABT-594 makes it through clin- leum generation from a source rock ical trials," he says, "it represents a funda- based on its organic sulfur content," says mentally novel mechanism" for modulat- Lewan. ing pain. Seewald, who comments on the reMairin Brennan search in the same issue of Nature, points out that the conditions Lewan uses are important. "They facilitate secondary reactions between alteration products and initial reactants and therefore more closely replicate conditions in natural systems where alteration prodModels for predicting the location of oil ucts are not rapidly removed from the and natural gas deposits may have to be site of generation," he says. modified now that experimental eviLewan notes that his results "imply dence shows sulfur radicals play a key that kinetic parameters determined by role in controlling the rate of petroleum nonisothermal open-system pyrolysis, formation. which are commonly employed in peMichael D. Lewan, a research organic troleum exploration, are not applicable geochemist at the U.S. Geological Sur- to petroleum formation in sedimentary vey, Denver, has proposed a model to basins." account for the numerous hydrocarbon Seewald explains that predictive fragments found in petroleum [Nature, models used by the oil industry general391, 164 (1998)]. These fragments are ly assume that petroleum generation formed during petroleum generation and stability are influenced by time, through the thermal decomposition of temperature, and kerogen composition kerogen, the insoluble organic material alone. "Although Lewan limits his disburied in sedimentary basins. cussion to kerogen-derived sulfur radi"Conventional wisdom advocates that cals, there is no reason to believe that it is the weakness of C-S and S-S bonds other sources of initiating radicals are that is responsible for early petroleum not important," he says. "Now that it generation from sulfur-rich kerogen," Jef- has been demonstrated that sulfur spefrey S. Seewald, a geochemist at Woods cies play a critical role in regulating the Hole Oceanographic Institution in Massa- stability of hydrocarbons at elevated temperatures, it would be wise to inchusetts, tells C&EN. But according to Lewan, that explana- corporate these effects into predictive tion fails to account for the overall com- models." position of petroleum. He argues that the Michael Freemantle
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Sulfur-radical theory may aid oil exploration
