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A cost-efficient synthesis of simvastatin (2), starting from mevinolin (lovastatin) (1a) or its precursor mevinolinic acid (1b), is reported. This synthesis involves the use of a new intermediate, lovastatin cyclopropylamide (3), eliminating two chemical steps of protection and deprotection of the open dihydroxy form of (1a). Synthesis is based on the high-conversion methylation of an alkoxide ester enolate and involves only four chemical steps. Methylation reaction conditions have been optimized to get >99.5% conversion. Process is economical on large-scale and product (2) is obtained in 85% overall yield.

The development of cross-tolerance to various alcohols and pentobarbital was examined in ethanol (EtOH)-treated mice. Chronic EtOH treatment (dosage rising in steps from 3.5-4.5 g/kg i.p. daily during a 23-day period) produced tolerance to its hypnotic effect. Such tolerance was seen as a reduction in the duration of loss of righting reflex (LRR), as well as higher blood EtOH levels at the offset of LRR, in EtOH-treated mice as compared to saline-treated controls. Cross-tolerance was shown by shifts in dose-response curves for the LRR induced by n-propanol and t-butanol. Such treatment, however, did not confer functional cross-tolerance to n-butanol and pentobarbital. Because n-butanol and pentobarbital are more lipid-soluble, whereas EtOH, n-propanol and t-butanol have low degrees of lipid solubility, the development of cross-tolerance among these sedative-hypnotic drugs might be related to their relative degrees of lipid solubility.

The passive and synaptic membrane properties of hippocampal CA1 and dentate gyrus granule neurons have been compared in hippocampal slices obtained from control and ethanol-tolerant rats given ethanol up to 24 hr before sacrifice. In addition, the effects of in vitro exposure to a low concentration (20 mM) of ethanol have been examined in neurons obtained from both groups of animals. No differences were observed in the passive or synaptic membrane properties of dentate granule neurons obtained from control and chronically ethanol-exposed rats. Dentate granule neurons obtained from the two groups of animals also showed similar responses to in vitro exposure to 20 mM ethanol. Hippocampal CA1 neurons were also similar, except for the post-spike train afterhyperpolarization which was significantly prolonged in neurons from chronically ethanol-exposed animals. Exposure to 20 mM ethanol in vitro resulted in a significant increase in the amplitude and duration of the afterhyperpolarization in CA1 neurons obtained from control animals, but a significant decrease in CA1 neurons obtained from chronically ethanol-exposed rats. These results suggest that behavioral tolerance to ethanol is accompanied by adaptive changes in the electrophysiological responses of hippocampal CA1 neurons when tested with an acute exposure to ethanol. Chronic treatment with ethanol did not cause such adaptive changes in dentate gyrus granule neurons suggesting that they may be less sensitive to the effects of long-term exposure to ethanol than CA1 neurons.

Electrolytic lesions were made in the median, the dorsal, the dorsal + median or magnus raphe nuclei of rats. Sham-control animals were also prepared through the same procedure with the exception that no current was delivered. After 1 week of recovery from surgery, a dose-response curve to the hypothermic and motor-impairment effects (moving belt test) was carried out to assess the initial response to ethanol. The maximal fall in temperature and maximum motor impairment were used to quantify the ethanol effects. Two days after the dose-response study, hypothermia and motor impairment were again determined in all animals after a test dose of ethanol. The animals in each main treatment group were than divided into two subgroups matched on the basis of their maximum hypothermic or motor impairment response. The subgroups received daily treatment with either ethanol (5 g/kg p.o.) or calorically equivalent amounts of sucrose. Tolerance to the ethanol-induced hypothermia or motor impairment was assessed at intervals of 5 days for 25 days. Lesions of the dorsal and magnus raphe nuclei produced a negligible effect on the development of ethanol tolerance. Lesions of the median raphe nucleus delayed the development of tolerance. Combined lesions of the median + dorsal raphe nuclei did not significantly increase the effect produced by the lesions of the median raphe nuclei alone. Biochemical analysis confirmed the differential depletion of 5-hydroxytryptamine by the various lesions. These results indicate that the 5-hydroxytryptamine pathway from the median raphe nucleus to the dorsal hippocampus is important in the development of tolerance to ethanol.

A novel and efficient synthesis of 4-substituted 2-oxazolidinones is described; the synthesis utilizes Sharpless asymmetric dihydroxylation (AD) of appropriately substituted O-allylcarbamates and intramolecular cyclisation as key steps.