We have compared the effects of
thiophene 2-carboxylic
acid (TCA) and a number of
sulfur- and
nitrogen-containing analogs for their ability to inhibit
bone resorption in organ cultures of fetal rat long bones. Four compounds,--thionaphthene-2-carboxylic
acid (TNCA), dibenzo-thiophene-4-carboxylic
acid,
indole-2-carboxylic acid and carbazole-1-carboxylic
acid--caused a dose-related inhibition of PTH-stimulated
bone resorption, although TCA was ineffective in this system. TNCA at 3 X 10(-4) M or 10(-4) M was the most potent inhibitor of PTH-stimulated
bone resorption and was selected for further study. TNCA also inhibited stimulation of resorption by
prostaglandin E2 and
1,25-dihydroxyvitamin D. Unlike
calcitonin, the effect of TNCA was persistent and did not show escape. Moreover, TNCA could inhibit resorption in bones that had previously escaped from
calcitonin. TNCA did not appear to be a nonspecific toxin, since it did not decrease incorporation of [3H]
thymidine or [3H]
proline into fetal rat long bones. The fact that resorption in unstimulated cultures was only decreased when the control rates were high also argues against nonspecific toxicity. Moreover, this suggests that TNCA will be most effective under conditions of accelerated
bone resorption when an inhibiting effect is most desirable.