Many higher plants produce economically important organic compounds such as oils, resins, tannins, natural rubber, gums, waxes, dyes, flavors and fragrances, pharmaceuticals, and pesticides. However, most species of higher plants have never been described, much less surveyed for chemical or biologically active constituents, and new sources of commercially valuable materials remain to be discovered. Advances in biotechnology, particularly methods for culturing plant cells and tissues, should provide new means for the commercial processing of even rare plants and the chemicals they produce. These new technologies will extend and enhance the usefulness of plants as renewable resources of valuable chemicals. In the future, biologically active plant-derived chemicals can be expected to play an increasingly significant role in the commercial development of new products for regulating plant growth and for insect and weed control.

Parathyroid hormone (PTH) secretion is regulated by a cell surface Ca 2؉ receptor that detects small changes in the level of plasma Ca 2؉ . Because this G protein-coupled receptor conceivably provides a distinct molecular target for drugs useful in treating bone and mineral-related disorders, we sought to design small organic molecules that act on the Ca 2؉ receptor. We discovered that certain phenylalkylamine compounds, typified by NPS R-568 and its deschloro derivative NPS receptor are termed calcimimetics. The discovery of calcimimetic compounds with potent and selective activity enables a pharmacological approach to regulating plasma levels of PTH. Calcimimetic compounds could conceivably provide a specific medical therapy for primary hyperparathyroidism.The concentration of ionized calcium (Ca 2ϩ ) in plasma is regulated largely by parathyroid hormone (PTH), which acts on the kidney and on bone to increase the level of plasma Ca The Ca 2ϩ receptor is a member of the G protein-coupled receptor superfamily and possesses an unusually large extracellular domain, the characteristic seven transmembrane domain, and a relatively long cytoplasmic tail. In these topological aspects, the Ca 2ϩ receptor is similar to metabotropic glutamate receptors (mGluR), although the sequence homology between these receptors is only about 25%. The human (1,078 amino acids) and bovine (1,085 amino acids) parathyroid cell Ca 2ϩ receptors are glycosylated proteins of ϳ120 kDa and are 93% identical (5). The Ca 2ϩ receptor expressed on authentic parathyroid cells or in heterologous cellular systems couples to phospholipase C and, when activated by increased concentrations of extracellular Ca 2ϩ , elicits rapid increases in inositol 1,4,5-trisphosphate and [Ca 2ϩ ] i (2, 4, 6). Thus, in its functional and structural properties, the parathyroid Ca 2ϩ receptor is akin to other cell surface receptors that initially transduce extracellular signals into functional cellular responses. The difference is that the physiological ligand for the Ca 2ϩ receptor is an inorganic ion, rather than an organic molecule.G protein-coupled receptors have been a classic site of action for drugs useful in treating various diseases. As a member of the G protein-coupled receptor superfamily, the Ca 2ϩ receptor is seemingly an ideal target for new pharmaceuticals useful in treating disorders of bone and mineral metabolism, such as hyperparathyroidism and osteoporosis. At present, however, the only ligands known to act on the Ca 2ϩ receptor are other inorganic di-and trivalent cations (2, 7) and organic polycations (8-10) that are nonselective and lack utility as systematic therapeutics. The present report describes the results of our initial efforts to devise a small organic compound that selectively acts on the parathyroid Ca 2ϩ receptor yet lacks a polycationic structure. NPS R-467 and NPS R-568 (Fig. 1) are two compounds that emerged from this effort. They are potent and selective activators of the Ca 2ϩ receptor and inhibit PTH secretion in vitro....

Calcimimetic compounds, which activate the parathyroid cell Ca 2ϩ receptor (CaR) and inhibit parathyroid hormone (PTH) secretion, are under experimental study as a treatment for hyperparathyroidism. This report describes the salient pharmacodynamic properties, using several test systems, of a new calcimimetic compound, cinacalcet HCl. Cinacalcet HCl increased the concentration of cytoplasmic Ca 2ϩ ([Ca 2ϩ ] i ) in human embryonic kidney 293 cells expressing the human parathyroid CaR. Cinacalcet HCl (EC 50 ϭ 51 nM) in the presence of 0.5 mM extracellular Ca 2ϩ elicited increases in [Ca 2ϩ ] i in a dose-and calcium-dependent manner. Similarly, in the presence of 0.5 mM extracellular Ca 2ϩ , cinacalcet HCl (IC 50 ϭ 28 nM) produced a concentration-dependent decrease in PTH secretion from cultured bovine parathyroid cells. Using rat medullary thyroid carcinoma 6-23 cells expressing the CaR, cinacalcet HCl (EC 50 ϭ 34 nM) produced a concentrationdependent increase in calcitonin secretion. In vivo studies in rats demonstrated cinacalcet HCl is orally bioavailable and displays approximately linear pharmacokinetics over the dose range of 1 to 36 mg/kg. Furthermore, this compound suppressed serum PTH and blood-ionized Ca 2ϩ levels and increased serum calcitonin levels in a dose-dependent manner. Cinacalcet was about 30-fold more potent at lowering serum levels of PTH than it was at increasing serum calcitonin levels. The S-enantiomer of cinacalcet (S-AMG 073) was at least 75-fold less active in these assay systems. The present findings provide compelling evidence that cinacalcet HCl is a potent and stereoselective activator of the parathyroid CaR and, as such, might be beneficial in the treatment of hyperparathyroidism.

The natural world once served as the source of all medicinal agents, with higher plants constituting by far the principal sources of these. Today, higher plants continue to retain their historical significance as important sources of novel compounds useful directly as medicinal agents, as model compounds for synthetic or semisynthetic structure modifications and optimization, as biochemical and/or pharmacological probes, and as sources of inspiration for generations of synthetic organic medicinal chemists. Plant-derived compounds which have recently undergone development include the anticancer agents, taxol and camptothecin, the Chinese antimalarial drug, artemisinin, and the East Indian Ayurvedic drug, forskolin. These and many other examples serve to illustrate the continuing value of plant-derived secondary metabolites as viable compounds for modern drug development.Higher plants have served humankind as sources of medicinal agents since its earliest beginnings. In fact, natural products once served as the source of all drugs. Today, natural products (and their derivatives and analogs) still represent over 50% of all drugs in clinical use, with higher plant-derived natural products representing ca. 25% of the total. On numerous occasions, the folklore records of many different cultures have provided leads to plants with useful medicinal properties (1-11). In the past two centuries, the chemical investigation and purification of extracts of plants purported to have medicinal properties, and those used as toxins and hunting poisons in their native habitats, have yielded numerous purified compounds which have

The mosquito feeding and ovipositional repellency of the major monoterpenoid present in the volatile oil ofHemizonia fitchii (Asteraceae), i.e., 1,8-cineole, was investigated. Although 1,8-cineole did not exhibit any significant mosquito larvicidal activity, it was moderately effective as a feeding repellent and highly effective as an ovipositional repellent against adultAedes aegypti (yellow fever mosquito). The ovipositional repellency of 1,8-cineole, coupled with the presence of severalHemizonia chromenes previously shown to possess mosquito larvicidal activity, may therefore account in large part for the observed suppression of local mosquito populations which was associated withH. fitchii plants in northern California.