Salvinorin A is a unique hallucinogen that is seeing increased use in humans. It is not currently a controlled substance and is used as a legal alternative to controlled substances. Usually smoked or buccally absorbed by chewing, doses of approximately 200 mcg can produce profound hallucinogenic effects of short duration. The mechanism of action of salvinorin A is at the kappa-opioid receptor. Little data is available on the medical effects of this substance so animal studies were undertaken to explore the acute toxic effects of this substance in rats and the chronic effects in mice. Rats were anesthetized and administered salvinorin A at 1600 mcg/kg or vehicle. Recordings were made of galvanic skin response, EKG, temperature, and pulse pressure for 100 minutes. Mice were chronically exposed to vehicle or 400, 800, 1600, 3200, or 6400 mcg/kg of salvinorin A for two weeks. After exposure the animals were sacrificed and brain, heart, kidney, bone marrow, blood and spleen were removed, fixed, sectioned, stained and examined by light microscopy. No effects were seen on cardiac conduction, temperature, or galvanic skin response. A nonsignificant rise was seen in pulse pressure. Histologic studies of spleen, blood, brain, liver, kidney, and bone marrow did not find any significant histologic changes at any of the doses examined. These data suggests that the toxicity of salvinorin A is relatively low, even at doses many times greater than what humans are exposed to. However, further studies should be done on blood pressure effects. The psychological impact of this potent hallucinogen should also be investigated.

The synthesis and in vitro anti-tumor 60 cell lines screen of a novel series of anthracenyl isoxazole amides (AIMs)¥ (22-33) is described. The molecules consist of an isoxazole that pre-organizes a planar aromatic moiety and a simple amide and/or lexitropsin-oligopeptide. The new conjugate molecules were prepared via doubly activated amidation modification of Weinreb's amide formation technique, using SmCl 3 as an activating agent which produces improved yields for sterically hindered 3-aryl-4-isoxazolecarboxylic esters. The results of the National Cancer Institute's (NCI) 60 cell line screening assay show a distinct structure activity relationship (SAR), wherein a trend of the highest activity for molecules with one N-methylpyrrole peptide. Evidence consistent with a mechanism of action via the interaction of these compounds with G-quadruplex (G4) DNA, and a structural based rational for the observed selectivity of the AIMs for G4 over B-DNA is presented.

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Previous studies based upon competition between different organic anions for biliary excretion in vivo have suggested that all organic anions share a common hepatic secretory mechanism. Corriedale sheep with an inherited defect in organic anion excretion by the liver were used to study this problem directly without the need for competition studies, the results of which are difficult to analyze. Maximal biliary excretion of sulfobromphthalein (BSP) in mutant Corriedale sheep was less than 7% of that observed in normal sheep whereas maximal biliary excretion of taurocholate, the major organic anion in sheep bile, was not different in mutant and normal sheep. Taurocholate infusion enhanced maximal hepatic excretion of BSP in normal but not in mutant sheep. These studies of an inheritable disorder which appears to be identical to the Dubin-Johnson syndrome in man, demonstrate that taurocholate excretion requires at least one step in biliary excretion which is not required by other organic anions such as bile pigment, porphyrins, drugs, and dyes.The organic anions in m a m m a l i a n bile consist of bile acids, bile pigments, porphyrins, metabolites, dyes, and drugs which are believed to be excreted by the parenchymal liver cell (1-3) and which are present in bile in concentrations very much greater than their simultaneous concentrations in plasma (2). It has been proposed that the organic anions excreted in bile share a common secretory mechanism because of their similarity to the group of compounds secreted by the renal organic anion transport mechanism (4), although bile salts are actively reabsorbed by the kidney tubule whereas phenol red, another organic anion, is actively secreted (5). Parenteral administration of some organic anions depresses the biliary excretion of other organic anions when administered simultaneously (2). Demonstration of competition for biliary excretion in vivo between different organic anions is complicated because m a n y of these compounds may share common binding to serum proteins, mechanisms of entry into liver cells, and various intraceUular metabolic trans-238

Pyridinium chlorochromate oxidation of 9‐methylacridine (2) affords the corresponding aldehyde 3 in good yield. Conversion of the aldehyde to the hydroximinoyl chloride 5a was accomplished via reaction of the corresponding oxime with N‐chlorosuccinimide. Dipolar addition to the enamine of ethylacetoacetate provided the corresponding isoxazoles 1 in good yield.

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