Structural modifications of the retinoid X receptor (RXR) selective compound 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2- naphthyl)ethenyl]benzoic acid (LGD1069), which is currently in phase I/IIA clinical trials for cancer and dermatological indications, have resulted in the identification of increasingly potent retinoids with > 1000-fold selectivity for the RXRs. This paper describes the design and preparation of a series of RXR selective retinoids as well as the biological data obtained from cotransfection and competitive binding assays which were used to evaluate their potency and selectivity. The most potent and selective of the analogs is 6-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2- yl)cyclopropyl]nicotinic acid (12d; LG100268). This compound has proven useful for investigating RXR dependent biological pathways including the induction of programmed cell death (PCD) and transglutaminase (TGase) activity. Our studies indicate that the induction of PCD and TGase in human leukemic myeloid cells is dependent upon activation of RXR-mediated pathways.

The spirochetes found in dental plaque from patients with ulcerative gingivitis or chronic periodontitis have antigens that are thought to be unique to pathogenic treponemes. This close antigenic relation suggests that T. pallidum or a closely related organism may be involved in the pathogenesis of periodontal disease.

Prior investigations have demonstrated that salivary antibody responses to mutans streptococci are dose-dependent and temporary. The purpose of this study was to evaluate the stability of antibody suppression established by mutans streptococci. Streptococcus mutans 6715-15 was provided in food to conventional rats for 18 weeks. Antigen was withdrawn for 10 weeks and then resumed for an additional 6 weeks. Saliva and serum from nonimmunized controls and from experimental rats were tested with a quantitative enzyme-linked immunosorbent assay for IgA and IgG antibodies to whole bacterial cells and to soluble antigen. Results show that salivary antibodies were stimulated by primary peroral immunization, that IgA was the dominant isotype and that IgA antibodies were primarily directed against soluble antigen. This study also shows that immunity is not maintained, even while challenge continues, and that once suppression is established, immunized animals do not recover their ability to respond, even if exposure is stopped for 10 weeks before re-exposure.

Conventional outbred rats were fed Streptococcus sobrinus for 24 weeks and ELISA was used to identify isotypes of antibodies against bacteria in saliva and serum. Quantities of antibodies from experimental rats were compared with values derived from the control population. Saliva IgM and IgA anti-S. sobrinus from experimental rats were greater than controls at week 3, were much less at week 9, but normal levels were found by week 13. IgG antibodies in saliva peaked at weeks 5 and 9 but fell to control levels by week 13. Relative levels of antibodies in saliva of experimental animals continued to cycle during weeks 13-24 but did not differ greatly from controls. Serum IgM and IgG antibodies to S. sobrinus were essentially like controls throughout the experiment. Serum IgA increased briefly during the first 12 weeks then returned to normal levels. The results suggest that prolonged peroral exposure to cariogenic bacteria ultimately leads to modulation of antibody around unimmunized control levels even though antigenic stimulation persists.

SUMMARY[3H]RU38486 (RU486) was synthesized from its penultimate precursor, desmethyl RU486, by substitution of the secondary amine with tritiated methyl iodide: specific activity 85 CVmmol. Ligand binding studies confirm that RU486 binds with high affinity to human progesterone receptor type A (PR-A) and progesterone receptor type B (PR-B).