Structure--activity studies for alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropanoic acid receptors: acidic hydroxyphenylalanines.

Antagonists of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropanoic acid (AMPA) receptors may have therapeutic potential as psychotropic agents. A series of mononitro- and dinitro-2- and 3-hydroxyphenylalanines was prepared, and their activity compared with willardiine, 5-nitrowillardiine, AMPA, and 2,4,5-trihydroxyphenylalanine (6-hydroxydopa) as inhibitors of specific [3H]AMPA and [3H]kainate binding in rat brain homogenates. The most active compounds were highly acidic (pKa 3-4), namely, 2-hydroxy-3,5-dinitro-DL-phenylalanine (13; [3H]AMPA IC50 approximately equal to 25 microM) and 3-hydroxy-2,4-dinitro-DL-phenylalanine (19; [3H]AMPA IC50 approximately equal to 5 microM). Two other dinitro-3-hydroxyphenylalanines, and 3,5-dinitro-DL-tyrosine, were considerably less active. Various mononitrohydroxyphenylalanines, which are less acidic, were also less active or inactive, and 2- and 3-hydroxyphenylalanine (o- and m-tyrosine) were inactive. Compounds 13 and 19, DL-willardiine (pKa 9.3, [3H]AMPA IC50 = 2 microM), and 5-nitro-DL-willardiine (pKa 6.4, [3H]AMPA IC50 = 0.2 microM) displayed AMPA >> kainate selectivity in binding studies. Compound 19 was an AMPA-like agonist, but 13 was an antagonist in an AMPA-evoked norepinephrine release assay in rat hippocampal nerve endings. Also, compound 13 injected into the rat ventral pallidum antagonized the locomotor activity elicited by systemic amphetamine.

Stability of ondansetron hydrochloride injection in various beverages.

The stability of ondansetron hydrochloride injection in beverages likely to be acceptable to patients was studied. Ondansetron hydrochloride injection (containing ondansetron 2 mg/mL) was added to apple juice, fruit punch, cherry-flavored drink, carbonated soft drinks, and hot tea to provide a nominal ondansetron concentration of 32.8, 64.5, or 95.2 micrograms/mL. Samples were stored at -3 to 28 degrees C (noncarbonated-beverage mixtures except tea), 2 to 28 degrees C (carbonated-beverage mixtures), and 25 degrees C (tea) and assayed for ondansetron concentration by high-performance liquid chromatography at 6, 24, 48, and 72 hours (noncarbonated-beverage mixtures except tea); 6, 24, and 48 hours (carbonated-beverage mixtures); and 1 hour (tea). More than 95% of the initial ondansetron concentration was retained in apple juice, fruit punch, cherry-flavored drink, Sprite, and Diet Coke throughout the periods studied. A precipitate formed immediately after ondansetron was added to hot tea, but the drug was chemically stable for at least one hour in this preparation. Ondansetron hydrochloride injection 32.7, 64.5, and 95.2 micrograms/mL (expressed as free base) was stable in various beverages when stored at -3 to 28 degrees C for up to 72 hours. Ondansetron at these same concentrations precipitated in hot tea preparations but was chemically stable for at least one hour.