STRUCTURE-ACTIVITY-RELATIONSHIPS OF NEW HETEROCYCLE-CONTAINING BISPHOSPHONATES AS INHIBITORS OF BONE-RESORPTION AND AS INHIBITORS OF GROWTHOF DICTYOSTELIUM-DISCOIDEUM AMEBAS

The mechanisms by which bisphosphonate drugs inhibit osteoclast-mediat ed bone resorption are unclear. Effects of bisphosphonates on cellular enzymes, metabolic pathways, and osteoclast morphology have previousl y been described and could culminate in a generalized cytotoxic effect or a decreased capacity of osteoclasts to resorb bone. Recent studies of the structure-activity relationship for the bisphosphonate side ch ain indicate, however, that at least the newer generations of nitrogen -containing bisphosphonates probably act by binding to a specific targ et at a site that is complementary in structure to the bisphosphonate side chain. We have previously proposed that such a target for bisphos phonates is also present in amoebae of the cellular slime mold Dictyos telium discoideum, because growth of this microorganism is inhibited b y a wide range of bisphosphonates in a manner that closely reflects th e antiresorptive potencies of the bisphosphonates in vivo, We have add ed support for this view by examining the potency towards Dictyosteliu m of bisphosphonates in which slight changes in the structure of the s ide chain or conformational restrictions to the side chain have marked effects on antiresorptive potency. The changes in the side chain that affected the in vivo antiresorptive potency of the bisphosphonates co nsistently affected in a similar manner the potency of the bisphosphon ates as inhibitors of the growth of Dictyostelium amoebae. These obser vations confirm that bisphosphonate drugs have a molecular target that is common to both Dictyostelium amoebae and osteoclasts.