Identification and characterization of potent, selective, and efficacious inhibitors of human arylamine N-acetyltransferase 1.

Arylamine N-acetyltransferase 1 (NAT1) plays a pivotal role in the metabolism of carcinogens and is a drug target for cancer prevention and/or treatment. A protein-ligand virtual screening of 2 million chemicals was ranked for predicted binding affinity towards the inhibition of human NAT1. Sixty of the five hundred top-ranked compounds were tested experimentally for inhibition of recombinant human NAT1 and N-acetyltransferase 2 (NAT2).

Acetylation of putative arylamine and alkylaniline carcinogens in immortalized human fibroblasts transfected with rapid and slow acetylator N-acetyltransferase 2 haplotypes.

Exposure to alkylanilines found in tobacco smoke and indoor air is associated with risk of bladder cancer. Genetic factors significantly influence the metabolism of arylamine carcinogens and the toxicological outcomes that result from exposure. We utilized nucleotide excision repair (NER)-deficient immortalized human fibroblasts to examine the effects of human N-acetyltransferase 1 (NAT1), CYP1A2, and common rapid (NAT2*4) and slow (NAT2*5B or NAT2*7B) acetylator human N-acetyltransferase 2 (NAT2) haplotypes on environmental arylamine and alkylaniline metabolism.

Smoke Chemistry, In Vitro Cytotoxicity, and Genotoxicity Demonstrates Enhanced Toxicity of Cigarillos Compared With Cigarettes.

There has been limited toxicity testing of cigarillos, including comparison to cigarettes. This study compared the smoke chemistry and the cytotoxic and genotoxic potential of 10 conventional cigarettes and 10 cigarillos based on the greatest market share. Whole smoke and total particulate matter (TPM) were generated using the Canadian Intense and International Organization for Standardization puffing protocols.

Development of a Nicotinic Acetylcholine Receptor nAChR α7 Binding Activity Prediction Model.

Despite the well-known adverse health effects associated with tobacco use, addiction to nicotine found in tobacco products causes difficulty in quitting among users. Nicotinic acetylcholine receptors (nAChRs) are the physiological targets of nicotine and facilitate addiction to tobacco products. The nAChR-α7 subtype plays an important role in addiction; therefore, predicting the binding activity of tobacco constituents to nAChR-α7 is an important component for assessing addictive potential of tobacco constituents.

Biomarkers of Exposure among Adult Smokeless Tobacco Users in the Population Assessment of Tobacco and Health Study (Wave 1, 2013-2014).

Background: Monitoring population-level toxicant exposures from smokeless tobacco (SLT) use is important for assessing population health risks due to product use. In this study, we assessed tobacco biomarkers of exposure (BOE) among SLT users from the Wave 1 (2013-2014) of the Population Assessment of Tobacco and Health (PATH) Study.

Methods: Urinary biospecimens were collected from adults ages 18 and older.

Competitive docking model for prediction of the human nicotinic acetylcholine receptor α7 binding of tobacco constituents.

The detrimental health effects associated with tobacco use constitute a major public health concern. The addiction associated with nicotine found in tobacco products has led to difficulty in quitting among users. Nicotinic acetylcholine receptors (nAChRs) are the targets of nicotine and are responsible for addiction to tobacco products.

High-Throughput Patch Clamp Screening in Human α6-Containing Nicotinic Acetylcholine Receptors.

Nicotine, the addictive component of tobacco products, is an agonist at nicotinic acetylcholine receptors (nAChRs) in the brain. The subtypes of nAChR are defined by their α- and β-subunit composition. The α6β2β3 nAChR subtype is expressed in terminals of dopaminergic neurons that project to the nucleus accumbens and striatum and modulate dopamine release in brain regions involved in nicotine addiction.

Synthesis of [11C]SSR149415 and preliminary imaging studies using positron emission tomography.

SSR149415 was the first non-peptide vasopressin-(V(1b)) receptor antagonist reported. It has been used to probe the role of V(1b) receptors in animal models of depression, aggression, and stress-anxiety, and was progressed to clinical trials for the treatment of depression. Due to the interest in V(1b) receptors as a therapeutic target and the growing use of SSR149415 in preclinical research, we developed a method to label SSR145419 with carbon-11 and have studied its pharmacokinetics in non-human primates using positron emission tomography.

A Preliminary Assessment of the Structure-Activity Relationship of Benzimidazole-Based Anti-Proliferative Agents.

PDK1 is pivotal in the development and progression of several cancers. A 3D pharmacophore was developed for pyrazole derivatives displaying anti-proliferative activity and PDK1 inhibition. The pharmacophore was utilized in the design of benzimidazole analogs.