Effects of 6-hydroxy-, 6-fluoro-, and 4,6-difluoromelatonin on the in vitro pituitary response to luteinizing hormone-releasing hormone.

The effects of 6-hydroxy-, 6-fluoro-, and 4,6-difluoromelatonin on the pituitary LH response to LHRH were studied in organ culture. Anterior pituitary glands obtained from 5-day-old female rats and maintained in culture in control medium for 24 h were incubated for an additional 6 h with the test substances. Medium LH content was determined by double antibody RIA. 6-Hydroxymelatonin, the primary metabolite of melatonin after iv administration, had no detectable effect on either basal or LHRH-stimulated release of LH when tested at concentrations up to 10(-6) M. This finding demonstrates that hydroxylation in position 6 will inactivate melatonin with regard to its pituitary effect. By contrast, 6-fluoro- and 4,6-difluoromelatonin at nanomolar concentrations both markedly suppressed the LH response to LHRH. Fluorine substitution for hydrogen in position 6, therefore, does not detectably interfere with activation of the pituitary melatonin receptor. Furthermore, in view of the increased strength of the carbon-fluorine bond compared to the carbon-hydrogen bond, the 6-fluoro analogs should be less susceptible than melatonin to inactivation by hydroxylation in position 6. These analogs, therefore, may be useful as long acting inhibitors of reproductive function in the intact animal.