E. Jon Jacobsen

Two representative compounds from a novel chemical series of potent inhibitors of lipid peroxidation are described. The compounds 21-[4-(2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-piperazinyl]-16 alpha-methylpregna-1,4,9(11)-triene-3,20-dione monomethane sulfonate (U74006F) and 21-[4-(3,6-bis(diethylamino)-2-pyridinyl)-1-piperazinyl]-16 alpha-methylpregna-1,4,9(11)triene-3,20-dione hydrochloride (U74500A) inhibited lipid peroxidation in brain homogenates and purified brain synaptosomes under a variety of conditions involving iron. With IC50 values ranging from 2 to 60 microM, U74006F and U74500A were comparable in potency to alpha-tocopherol or butylated hydroxytoluene and were nearly 100 times as potent as desferrioxamine. Some specificity for intact phospholipid membranes is suggested since the ability of U74006F or U74500A to inhibit lipid peroxidation was greatly reduced in methanol solutions of arachidonic acid. Despite close similarities in their structures, their response to increasing concentrations of Fe2+ in lipid peroxidation assays differed qualitatively. One of the compounds, U74500A, may act as a membrane localized chelator of iron.

N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide (14, PHA-543,613), a novel agonist of the alpha7 neuronal nicotinic acetylcholine receptor (alpha7 nAChR), has been identified as a potential treatment of cognitive deficits in schizophrenia. Compound 14 is a potent and selective alpha7 nAChR agonist with an excellent in vitro profile. The compound is characterized by rapid brain penetration and high oral bioavailability in rat and demonstrates in vivo efficacy in auditory sensory gating and, in an in vivo model to assess cognitive performance, novel object recognition.