Polyploidy influences plant-environment interactions in quaking aspen (Populus tremuloides Michx.).

Quaking aspen (Populus tremuloides Michx.), a widespread and keystone tree species in North America, experienced heat and drought stress in the years 2002 and 2003 in the southwestern United States. This led to widespread aspen mortality that has altered the composition of forests, and is expected to occur again if climate change continues.

When to walk away from a deal.

Deal making is glamorous; due diligence is not. That simple statement goes a long way toward explaining why so many companies have made so many acquisitions that have produced so little value. The momentum of a transaction is hard to resist once senior management has the target in its sights.

Raloxifene and estrogen inhibit neointimal thickening after balloon injury in the carotid artery of male and ovariectomized female rats.

The effects of raloxifene and 17alpha-ethinyl estradiol (EE2) on intimal thickening in response to balloon injury were tested in male and ovariectomized female rats. In male rats, oral raloxifene and EE2, administered either by gavage or in the diet, inhibited arterial intimal thickening in response to balloon injury to a maximum of approximately 60 and 50%, respectively. The effect of oral raloxifene to decrease cholesterol was observed at doses (> or = 3 mg/kg/day) higher than those required to inhibit intimal thickening (> or = 0.

Molecular determinants of tissue selectivity in estrogen receptor modulators.

Interaction of the estrogen receptor/ligand complex with a DNA estrogen response element is known to regulate gene transcription. In turn, specific conformations of the receptor-ligand complex have been postulated to influence unique subsets of estrogen-responsive genes resulting in differential modulation and, ultimately, tissue-selective outcomes. The estrogen receptor ligands raloxifene and tamoxifen have demonstrated such tissue-specific estrogen agonist/antagonist effects.

LY320135, a novel cannabinoid CB1 receptor antagonist, unmasks coupling of the CB1 receptor to stimulation of cAMP accumulation.

LY320135 is a selective antagonist for the brain CB1 receptor, having greater than 70-fold higher affinity for the CB1 than the peripheral CB2 receptor. The Ki values for LY320135 at the CB1 and CB2 receptors, transfected and stably expressed in cell lines, were 224 nM and > 10 microM, respectively. Similar Ki values were measured in binding studies performed on cerebellum and spleen membrane preparations endogenously expressing the CB1 (203 nM) and CB2 (> 10 microM) receptors, respectively.

Discovery and synthesis of [6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]b enzo[b]thiophene: a novel, highly potent, selective estrogen receptor modulator.

Raloxifene,[2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl] [4-[2-(1-piperidinyl)ethoxy]phenyl]methanone hydrochloride (2), is representative of a class of compounds known as selective estrogen receptor modulators (SERMs) that possess estrogen agonist-like actions on bone tissues and serum lipids while displaying potent estrogen antagonist properties in the breast and uterus. As part of ongoing SAR studies with raloxifene, we found that replacement of the carbonyl group with oxygen ([6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]b enzo[b]thiophene hydrochloride, 4c) resulted in a substantial (10-fold) increase in estrogen antagonist potency relative to raloxifene in an in vitro estrogen dependent cell proliferation assay (IC50 = 0.05 nM) in which human breast cancer cells (MCF-7) were utilized.

Hypocholesterolemic activity of raloxifene (LY139481): pharmacological characterization as a selective estrogen receptor modulator.

After once-daily oral dosing in ovariectomized rats, raloxifene (LY139481) hydrochloride produced dose- and time-dependent reductions in serum cholesterol and high-density lipoprotein-cholesterol. Paired-feeding studies demonstrated that effects of raloxifene on serum lipids were not secondary to effects on food consumption. Maximal reductions in serum cholesterol occurred within 4 days of raloxifene administration or sooner, depending on the administered dose.

Raloxifene (LY139481 HCI) prevents bone loss and reduces serum cholesterol without causing uterine hypertrophy in ovariectomized rats.

There is a medical need for an agent with the positive effects of estrogen on bone and the cardiovascular system, but without the negative effects on reproductive tissue. Raloxifene (LY139481 HCI) is a benzothiophene derivative that binds to the estrogen receptor and inhibits the effects of estrogen on the uterus. In an ovariectomized (OVX) rat model we investigated the effects of raloxifene on bone loss (induced by estrogen deficiency), serum lipids, and uterine tissue.

New antitumor monoclonal antibody-vinca conjugates LY203725 and related compounds: design, preparation, and representative in vivo activity.

A method has been developed to allow the direct coupling of the cytotoxic vinca alkaloid 4-desacetylvinblastine-3-carbohydrazide (DAVLB hydrazide) to a variety of murine monoclonal antibodies directed against human solid tumors. Periodate oxidation of carbohydrate residues on the antibodies, followed by reaction with DAVLB hydrazide in aqueous acid affords, in most cases, conjugates with conjugation ratios of 4-6 vincas per antibody in high yield without significantly impairing antigen binding or solubility. The outcome of the conjugation reaction is highly dependent on the concentration of, and time of exposure of the protein to, the oxidant.

Leukotriene receptor antagonists. 1. Synthesis and structure-activity relationships of alkoxyacetophenone derivatives.

A series of derivatives of 2,4-dihydroxy-3-propylacetophenone(1) were prepared and examined for their ability to block leukotriene D4 (LTD4) induced contraction of guinea pig ileum. Straight-chain carboxylic acids where the carboxyl group was separated from the acetophenone moiety by varying numbers of methylenes were evaluated, and maximum activity was obtained with the pentamethylene acid (6). Examination of ring substitution showed that the 2-propyl-3-hydroxy-4-acetyl substitution pattern was required for maximum LTD4 antagonist activity.

Pharmacologic analysis of two novel inhibitors of leukotriene (slow reacting substance) release.

LY83583 , a quinolinedione , and LY151364 , a quinoxalinedione , were developed as inhibitors of leukotriene (slow reacting substance of anaphylaxis) release. They preferentially inhibited the release of leukotrienes over histamine from fragmented guinea-pig lung and rat peritoneal cells in vitro, regardless of whether the mediators were released immunologically by antigen or chemically by the divalent cationic ionophore, A23187. Similar results were obtained with rat peritoneal cells in vivo.

Structure-activity relationships of dimeric Catharanthus alkaloids. 2. Experimental antitumor activities of N-substituted deacetylvinblastine amide (vindesine) sulfates.

While structure-activity relationships for vinblastine (VLB), vincristine, deacetyl-VLB, and deacetyl-VLB amide (vindesine, VDS) in several tumor and leukemia models have been reported previously, the present study explores these relationships for a series of N-substituted vindesine analogues. These compounds were prepared from the reaction of deacetyl-VLB acid azide with the appropriate amines and were characterized by mass spectral analysis, 1H and 13C NMR spectra, electrometric titration, and infrared spectra. N-Alkylvindesines have reduced activity compared to that of VDS against the Gardner lymphosarcoma (GLS).

Structure-activity relationships of dimeric Catharanthus alkaloids. 1. Deacetylvinblastine amide (vindesine) sulfate.

Exploration of the effects of "minor" structural differences on the antitumor activity and toxicity of dimeric Catharanthus alkaloids resulted in the preparation of deacetylvinblastine amide (vindesine, VDS) from either vinblastine (VLB) or deacetylvinblastine. Adequate amounts of vindesine for biological testing were prepared by preferential hydrazinolysis of the C23-ester in the vindoline moiety of VLB, followed by hydrogenolysis of the resulting deacetylvinblastine hydrazide. Vindesine in its activity spectrum against rodent tumor systems resembles vincristine (VCR) rather than its parent VLB, while its neurotoxic potential appears to be less than that of VCR.