SBIR-STTR Award

Recent studies have provided evidence for the presence of a Ca2+ receptor on the surface of parathyroid cells which enables these cells to detect small changes in the concentration of extracellular Ca2+ and thereby alter parathyroid hormone secretion. This Ca2+ receptor is coupled to the mobilization of intracellular Ca2+ and shows many of the biochemical features common to more conventional Ca2+ mobilizing receptors. The only agents known to act at the Ca2+ receptor are di- and trivalent metal cations. The proposed studies examine the possibility that certain organic compounds might behave similarly to extracellular Ca2+ and regulate PTH secretion by acting as ligands at the Ca2+ receptor. Organic polycations (most notably spermine) will be examined for their ability using bovine and human parathyroid cells to: 1) mobilize intracellular Ca2+; 2) increase inositol phosphate formation; 3) decrease cyclic AMP formation; and 4) inhibit PTH secretion. Comparisons of these results will be made with those obtained with extracellular Ca2+ to determine if both organic and inorganic agents react through the same receptor-dependent mechanism. Organic compounds acting similarly to extracellular Ca2+ might then provide lead structures for the development of novel therapeutic agents effective in the treatment of various bone and mineral-related disorders such as hyperparathyroidism and osteoporosis.

Thesaurus Terms:
Amines, Spermine, Calcium (Mineral) Balance (Metabolism), Metal Complexes, Ligands, Parathyroid Glands, Parathyroid Hormones, Receptors Biological Transport, Intracellular Transport And Translocation, Body Fluids, Extracellular Space (Compartment), Calcium Flux (Cellular), Cell Fluids, Endocrinology, Hormonal Regulation And Control (Mechanisms), Endocrinology, Hormones Inhibitors, Ions, Polyions, Polycations, Purine Nucleotides, Adenine Nucleotides, Amp Cyclic, Sugar Alcohols, Hexitols, Inositol Phosphates, Receptor Binding, Receptor Coupling Animals, Chordates, Mammals, Ungulates, Cattle, Human, Human Tissues, Fluids Etc. From Non-Related Sources Outside Immediate Project

Recent studies demonstrate the presence of a calcium receptor protein on parathyroid cell that enables these cells to detect and respond to changes in the concentration of extracellular calcium. Drugs that act on this receptor to mimic the effects of extracellular calcium would offer a novel therapeutic approach to the treatment of hyperparathyroidism. In Phase I studies, it was shown that certain organic compounds were able to act on the calcium receptor and inhibit parathyroid hormone secretion. In Phase II, we plan to establish a database that defines the structural features of compounds that contribute to activity on the calcium receptor. This will be obtained by limited structure-activity studies on compounds shown to be effective in Phase I studies and by the testing of selected natural product compounds. We will clone the calcium receptor CDNA in order to obtain structural information about the receptor and to create transfected cell lines necessary for high-throughput screening of natural product libraries. The studies, which constitute the first description of the pharmacology and structure of the calcium receptor, will provide the technologies enabling a drug development program aimed at the discovery and design of drug candidates for the treatment of hyperparathyroidism.Awardee's statement of the potential commercial applications of the research:At present, the development of drug candidates that act on the parathyroid cell calcium receptor is hampered by a paucity of information concerning the structural features of compounds that activate it and the inability to rapidly and economically screen large numbers of compounds for activity. The Phase II studies will result in proprietary technologies that describe the pharmacology of the calcium receptor and that enable high-throughput screening of compound and natural product libraries.

Thesaurus Terms:
calcium, calcium binding protein, endocrine pharmacology, parathyroid gland, protein structure function, receptor calcium flux, chemical registry /resource, drug design /synthesis /production, hormone regulation /control mechanism, hyperparathyroidism, ligand, parathyroid hormone, receptor binding Xenopus oocyte, complementary DNA, human tissue, molecular cloning, transfection vector National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)