Natural plant chemicals: sources of industrial and medicinal materials.

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.

NPS 1506, a novel NMDA receptor antagonist and neuroprotectant. Review of preclinical and clinical studies.

NPS 1506 is a moderate affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. NPS 1506 is neuroprotective in rodent models of ischemic stroke, hemorrhagic stroke, and head trauma, with a 2-hr window of opportunity. Neuroprotectant doses of NPS 1506 ranged from approximately 0.1-1.0 mg/kg, with peak plasma concentrations ranging from 8-80 ng/mL. Even at doses producing behavioral toxicity, NPS 1506 did not elicit MK-801-like behaviors, did not generalize to phencyclidine (PCP), and did not elicit neuronal vacuolization. In a Phase I study, intravenous (i.v.) doses of NPS 1506 from 5-100 mg were well tolerated and provided plasma concentrations in excess of those required for neuroprotection in rodents. Adverse events at the 100-mg dose included mild dizziness and lightheadedness, and mild to moderate ataxia. Neither PCP-like psychotomimetic effects nor cardiovascular effects were noted. The long plasma half-life of NPS 1506 (approximately 60 hr) suggests that a single i.v. dose will provide prolonged neuroprotection in humans.

Valerian-derived sedative agents. I. On the structure and spectral assignment of the constituents of valmane using the selective INEPT nuclear magnetic resonance technique.

The valepotriates, a group of chemically unstable iridoid triesters possessing sedative activity, contain various ester groups at the C-1, C-7, and C-11 positions. Using the selective INEPT NMR technique and employing a suitable polarization delay for long-range coupling, it was possible to achieve the assignment and location of the ester groups directly, without ambiguity, and without chemical modification. Six valepotriates isolated from Valmane tablets served as examples to demonstrate the utility of this NMR technique. During the course of this work, the "acevaltrate" fraction was shown to be a mixture of 1-alpha-acevaltrate (3) and 7-beta-acevaltrate (4), the structures of valtrate (1) and didrovaltrate (2) were confirmed directly, and two new valepotriates, 5a and 5b, were obtained as an inseparable mixture and characterized.

1,8-Cineole (Eucalyptol), a mosquito feeding and ovipositional repellent from volatile oil ofHemizonia fitchii (Asteraceae).

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.

Reversed-phase high-pressure liquid chromatography of some tryptamine derivatives.

A quantitative reversed-phase high-pressure liquid chromatographic method is described for tryptamine, bufotenine, N-methyltryptamine and N,N-dimethyl tryptamine. All compounds were eluted with base-line separation within 15 min. The method is used to determine the tryptamine level in a leaf extract of Acacia podalyriaefolia A. Cunn. Satisfactory recoveries of tryptamine from plant material, and N,N-dimethyltryptamine from urine were obtained.

Insecticidal chromenes from the volatile oil ofHemizonia fitchii.

Based on field observations of the effects of the resinous tarweedHemizonia fitchii A. Gray (Asteraceae) on mosquito populations in California, the volatile oil of this plant was investigated for insecticidal activity. Analysis of thé oil by TLC and capillary GC-MS showed the presence of five major constituents which were identified as the monoterpenoid 1,8-cineole, and the chromenes encecalin, eupatoriochromene (desmethylencecalin), 6-vinyl-7-methoxy-2,2-dimethylchromene, and desmethoxyencecalin. Trace amounts of several volatile fatty acids, alkanes,p-coumarate derivatives, additional chromene derivatives, and numerous mono- and sesquiterpenoids were also detected and identified by GC-MS. Fractionation of the oil by preparative TLC and column chromatography afforded the major chromenes, the identities of which were confirmed by NMR and IR spectral data. The chromenes exhibited weak to moderate toxicity againstCulex pipiens (house mosquito) larvae andOncopeltus fasciatus (large milkweed bug) nymphs. However, no antijuvenile hormone activity was observed for any of the compounds tested against these insect species.

Calcimimetics with potent and selective activity on the parathyroid calcium receptor.

Parathyroid hormone (PTH) secretion is regulated by a cell surface Ca2+ receptor that detects small changes in the level of plasma Ca2+. 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 Ca2+ receptor. We discovered that certain phenylalkylamine compounds, typified by NPS R-568 and its deschloro derivative NPS R-467, increased the concentration of cytoplasmic Ca2+ ([Ca2+]i) in bovine parathyroid cells and inhibited PTH secretion at nanomolar concentrations. These effects were stereoselective and the R enantiomers were 10- to 100-fold more potent than the S enantiomers. NPS R-568 potentiated the effects of extracellular Ca2+ on [Ca2+]i and PTH secretion but was without effect in the absence of extracellular Ca2+. Both compounds shifted the concentration-response curves for extracellular Ca2+ to the left. Presumably, these compounds act as positive allosteric modulators to increase the sensitivity of the Ca2+ receptor to activation by extracellular Ca2+. Both NPS R-467 and NPS R-568 increased [Ca2+]i in HEK 293 cells expressing the human parathyroid Ca2+ receptor but were without effect in wild-type HEK 293 cells. Neither compound affected the cytoplasmic Ca2+ responses elicited by several other G protein-coupled receptors in HEK 293 cells or in bovine parathyroid cells. Significantly, these compounds did not affect responses elicited by the homologous metabotropic glutamate receptors, mGluR1a, mGluR2, or mGluR8. These compounds therefore act selectively on the Ca2+ receptor. Compounds that mimic or potentiate the effects of extracellular Ca2+ at the Ca2+ 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.

Synthesis, biological activity, and absolute stereochemical assignment of NPS 1392: a potent and stereoselective NMDA receptor antagonist.

The synthesis, biological activity, and single crystal X-ray structure of NPS 1392, (R)-(-)-3,3-bis(3-fluorophenyl)-2-methylpropan-1-amine (3a), a potent, stereoselective antagonist of the NMDA receptor, are described. The NMDA receptor selectively bound the levo isomer (3a) over its enantiomer (3b), which prompted a rigorous absolute configuration assignment. NPS 1392 has the R configuration based on the single-crystal X-ray diffraction analysis of the hydroiodide salt of NPS 1392. This compound is a potential neuroprotective agent for use in the treatment of ischemic stroke.

NPS 1506, a moderate affinity uncompetitive NMDA receptor antagonist: preclinical summary and clinical experience.

NPS Pharmaceuticals, Inc. (NPS) has synthesized a series of open-channel blockers with varying potencies at the NMDA receptor. NPS 1506 (Fig. 1) is a moderate affinity antagonist that inhibits NMDA/glycine-induced increases in cytosolic calcium in cultured rat cerebellar granule cells (IC50 = 476nM) and displaces the binding of [3H]MK-801 to rat cortical membranes (IC50 = 664nM).

Chiral synthesis and pharmacological evaluation of NPS 1407: a potent, stereoselective NMDA receptor antagonist.

The stereoselective synthesis and biological activity of NPS 1407 (4a), (S)-(-)-3-amino-1,1-bis(3-fluorophenyl)butane, a potent, stereoselective antagonist of the NMDA receptor, are described. The racemate (4) was found to be active at the NMDA receptor in an in vitro assay, prompting the synthesis of the individual stereoisomers. The S isomer (4a) was found to be 12 times more potent than the R isomer (4b). Compound 4a demonstrated in vivo pharmacological activity in neuroprotection and anticonvulsant assays.