piperidines and benzothiophene

Nicotinic acetylcholine receptor (nAChR) ligands that lack agonist activity but enhance activation in the presence of an agonist are called positive allosteric modulators (PAMs). nAChR PAMs have therapeutic potential for the treatment of nicotine addiction and several neuropsychiatric disorders. PAMs need to be selectively targeted toward certain nAChR subtypes to tap this potential. We previously discovered a novel PAM, (

Topics: Allosteric Regulation; Amino Acid Sequence; Animals; Binding Sites; Humans; Kinetics; Molecular Docking Simulation; Mutagenesis, Site-Directed; Nicotinic Agonists; Oocytes; Patch-Clamp Techniques; Piperidines; Protein Structure, Tertiary; Protein Subunits; Receptors, Nicotinic; Recombinant Proteins; Sequence Alignment; Thiophenes; Xenopus laevis

There is association between exposure to estrogens and the development and progression of hormone-dependent gynecological cancers. Chemical carcinogenesis by catechol estrogens derived from oxidative metabolism is thought to contribute to breast cancer, yet exact mechanisms remain elusive. Malignant transformation was studied in MCF-10A human mammary epithelial cells, since estrogens are not proliferative in this cell line. The human and equine estrogen components of estrogen replacement therapy (ERT) and their catechol metabolites were studied, along with the influence of co-administration of selective estrogen receptor modulators (SERMs), raloxifene and desmethyl-arzoxifene (DMA), and histone deacetylase inhibitors. Transformation was induced by human estrogens, and selectively by the 4-OH catechol metabolite, and to a lesser extent by an equine estrogen metabolite. The observed estrogen-induced upregulation of CYP450 1B1 in estrogen receptor negative MCF-10A cells, was compatible with a causal role for 4-OH catechol estrogens, as was attenuated transformation by CYP450 inhibitors. Estrogen-induced malignant transformation was blocked by SERMs correlating with a reduction in formation of nucleobase catechol estrogen (NCE) adducts and formation of 8-oxo-dG. NCE adducts can be formed consequent to DNA abasic site formation, but NCE adducts were also observed on incubation of estrogen quinones with free nucleotides. These results suggest that NCE adducts may be a biomarker for cellular electrophilic stress, which together with 8-oxo-dG as a biomarker of oxidative stress correlate with malignant transformation induced by estrogen oxidative metabolites. The observed attenuation of transformation by SERMs correlated with these biomarkers and may also be of clinical significance in breast cancer chemoprevention.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Biomarkers; Breast; Catechols; Cell Line; Cell Transformation, Neoplastic; Cytochrome P-450 Enzyme System; Deoxyguanosine; DNA Adducts; Enzyme Induction; Epithelial Cells; Estrogens; Female; Histone Deacetylase Inhibitors; Horses; Humans; Oxidation-Reduction; Oxidative Stress; Piperidines; Raloxifene Hydrochloride; Selective Estrogen Receptor Modulators; Thiophenes

The synthesis and structure-activity relationships (SAR) of a series of benzothiophene piperazine and piperidine urea FAAH inhibitors is described. These compounds inhibit FAAH by covalently modifying the enzyme's active site serine nucleophile. Activity-based protein profiling (ABPP) revealed that these urea inhibitors were completely selective for FAAH relative to other mammalian serine hydrolases. Several compounds showed in vivo activity in a rat complete Freund's adjuvant (CFA) model of inflammatory pain.

Topics: Amidohydrolases; Animals; Computer Simulation; Enzyme Inhibitors; Humans; Models, Chemical; Piperazines; Piperidines; Rats; Structure-Activity Relationship; Thiophenes; Urea

The benzothiophene selective estrogen receptor modulators (SERMs), raloxifene and arzoxifene, in the clinic or clinical trials for treatment of breast cancer and postmenopausal symptoms, are highly susceptible to oxidative metabolism and formation of electrophilic metabolites. 4'F-DMA, fluoro-substituted desmethyl arzoxifene (DMA), showed attenuated oxidation to quinoids in incubation with rat hepatocytes as well as in rat and human liver microsomes. Incubations of 4'F-DMA with hepatocytes yielded only one glucuronide conjugate and no GSH conjugates, whereas DMA underwent greater metabolism giving two glucuronide conjugates, one sulfate conjugate, and two GSH conjugates. Phase I and phase II metabolism were further evaluated in human small intestine microsomes and in human intestinal Caco-2 cells. In comparison to DMA, 4'F-DMA formed significantly less glucuronide and sulfate conjugates. The formation of quinoids was further explored in hepatocytes in which DMA was observed to give concentration- and time-dependent depletion of GSH accompanied by damage to DNA, which showed inverse dependence on GSH; in contrast, GSH depletion and DNA damage were almost completely abrogated in incubations with 4'F-DMA. 4'F-DMA shows ligand binding affinity to estrogen receptor (ER)alpha and ERbeta with similarity to both raloxifene and to DMA. ER-mediated biological activity was measured with the ERE-luciferase reporter system in transfected MCF-7 cells and Ishikawa cells, and in MCF-7 cells, proliferation was measured. In all systems, 4'F-DMA exhibited anitestrogenic activity of comparable potency to raloxifene but did not manifest estrogenic properties, mirroring previous results on inhibition of estradiol-mediated induction of alkaline phosphatase activity in Ishikawa cells. These results suggest that 4'F-DMA might be an improved benzothiophene SERM with similar antiestrogenic activity to raloxifene but improved metabolic stability and attenuated toxicity, showing that simple chemical modification can abrogate oxidative bioactivation to potentially toxic metabolites without loss of activity.

Topics: Animals; Cell Proliferation; Cells, Cultured; DNA Damage; Estrogen Receptor Modulators; Estrogens; Genes, Reporter; Humans; Intestine, Small; Microsomes; Molecular Structure; Oxidation-Reduction; Piperidines; Rats; Thiophenes

[reaction: see text] Benzo[b]thiophene derivatives are important in part because of their use as selective estrogen receptor modulators. They are usually synthesized by intramolecular cyclization. Here, we propose a method for the synthesis of 2-arylbenzo[b]thiophenes with heteroatoms at the 3-positions directly from the benzo[b]thiophene core by using an aromatic nucleophilic substitution reaction and Heck-type coupling. This methodology provides 2-aryl-3-amino or phenoxybenzo[b]thiophenes in about 35% overall yield in 5 steps.

Topics: Cyclization; Molecular Structure; Oxidation-Reduction; Piperidines; Raloxifene Hydrochloride; Selective Estrogen Receptor Modulators; Structure-Activity Relationship; Thiophenes