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Bioassay-guided fractionation of a methanolic extract of a Thai crude drug, derived from heartwood of Anaxagorea luzonensis A. Gray (Annonaceae), resulted in the isolation of 8-isopentenylnaringenin (1) as an estrogen agonist with a activity of about an order of magnitude greater than genistein. Various flavonoids possessing isopentenyl side chains in the A-ring have been prepared and evaluated for their ability to bind estrogen receptor. In addition, enantiomers of 1 were separated and the respective enantiomers were assayed. These studies have demonstrated that the presence of an 8-isopentenyl group is an important factor for binding. Flavones, flavanones and flavonols having an isopentenyl substituent at C-8 exhibited an appreciable affinity for estrogen receptor. Conversely, isoflavones possessing an 8-isopentenyl substituent at C-8 did not show this activity. Movement of the isopentenyl group from position 8 to 6 resulted in loss of the activity. No significant difference was observed between 2(S)- and 2(R)-enantiomers of 1 in their binding affinity. Prenylflavonoids are reported to possess a wide range of biological activities; however, estrogenic activity has not been described.

In order to examine whether 8-isopentenylnaringenin (1), which has been proven to possess estrogen agonist activity in in vitro tests, also produces in vivo estrogenic properties, the effects of 1 on uterus and on bone metabolism were determined in ovariectomized rats. Rats were ovariectomized and treated with 1 at 30 mg/kg/day subcutaneously for two weeks or 17 beta-estradiol at 0.01 mg/kg/day subcutaneously for two weeks. Ovariectomy resulted in an increase in urinary excretion of bone resorption markers (hydroxyproline, pyridinoline and deoxypyridinoline) and a decrease in bone mineral density of the proximal tibia as well as reduced uterine weight. Treatment with 1 or 17 beta-estradiol completely suppressed these ovariectomy-induced bone and uterine changes in a qualitatively similar manner. These results demonstrate that 1 acts as an estrogen agonist in the uterus as well as in bone in vivo.

A series of [2-[(omega-aminoalkoxy)phenyl]ethyl]benzene derivatives were synthesized and evaluated for their ability to inhibit collagen-induced platelet aggregation in vitro and to protect experimental thrombosis in mice. The results showed that the compounds were in vitro inhibitors of collagen-induced platelet aggregation. Most of them were also effective in the mouse antithrombotic assay. The compounds were found to be potent antagonists to S2 serotonergic receptor, and good correlation (r = 0.85) between their S2 serotonergic receptor antagonism and their potency as platelet antiaggregatory drugs was observed. Among the compounds studied, mono[2-(dimethylamino)-1-[[2-[2-(3- methoxyphenyl)ethyl]phenoxy]methyl]ethyl] succinate hydrochloride (12b, MCI-9042) was selected for further pharmacological and toxicological evaluation.

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Design and Syntheses of 4-Acylaminopyridine Derivatives: Novel High Affinity Choline Uptake Enhancers. Part 2.-Various analogues of the active lead compound (I) such as (II)-(IV) are synthesized and examined for high affinity choline uptake improvement. The oxopyrrolidinyl derivative (III) displays strong potency even at low concentrations and is currently in trials for Alzheimer disease treatment. -(CHAKI, H.; YAMABE, H.; SUGANO, M.; MORITA, S.; BESSHO, T.; TABATA, R.; SAITO, K.-I.; EGAWA, M.; TOBE, A.; MORINAKA, Y.; Bioorg. Med.

Design and Syntheses of 4-Acylaminopyridine Derivatives: Novel High Affinity Choline Uptake Enhancers. Part 1.-Various N-acyl derivatives of 9-amino-1,2,3,4-tetrahydroacridine, which is used in practice as AChE inhibitor for the treatment of Alzheimer's disease, are synthesized and examined for high affinity cholin uptake. The compounds (III), (VIII), and (X) are found to improve the reduced high affinity choline uptake in the hippocampal synaptosome of rats. -(CHAKI, H.; YAMABE, H.; SUGANO, M.; MORITA, S.; BESSHO, T.; TABATA, R.; SAITO, K.-I.; EGAWA, M.; TOBE, A.; MORINAKA, Y.; Bioorg. Med.