anatabine (RCP-006) / Rock Creek Pharma - LARVOL DELTA

Analysis and Toxicological Evaluation of Nicotine Degradants and Impurities in Oral Tobacco Products: A Case Study of on! PLUS Nicotine Pouches. (PubMed, ACS Omega) - "Anabasine, β-nicotyrine, anatabine, and nornicotine were either not detected or found below the limit of quantitation over the course of the stability study. Myosmine, cotinine, and nicotine-N'-oxide were found to be 0.055, 0.015, and 1.32% of the target nicotine level, respectively."

Journal

BBL enzymes exhibit enantiospecific preferences in the biosynthesis of pyridine alkaloids in Nicotiana tabacum L. (PubMed, Phytochemistry) - "In tobacco (Nicotiana tabacum L.), the pyridine alkaloids nicotine, nornicotine, anatabine, and anabasine naturally exist as scalemic mixtures of (R)- or (S)-enantiomers, with the (S)-isoforms predominating...Through a combination of mutation breeding and transgene overexpression, tobacco genotypes were generated in which the predominant alkaloid enantiomers were reversed from the (S)- to the (R)-isoforms. These results shed light on the genetic control of alkaloid accumulation in N. tabacum and on mechanisms of scalemic mixture formation of secondary metabolites in plants."

Journal

Development of an RNA virus vector for non-transgenic genome editing in tobacco and generation of berberine bridge enzyme-like mutants with reduced nicotine content. (PubMed, aBIOTECH) - "The decline of nicotine content in these lines was accompanied by reductions in anatabine and cotinine levels but increases in nornicotine and its derivative myosmine...Our work provides potentially valuable genetic materials for breeding low-nicotine tobacco and enhances our understanding of alkaloid biosynthesis. The online version contains supplementary material available at 10.1007/s42994-024-00188-y."

Journal

On the greenness of separation modes containing compressed fluids. (PubMed, Anal Chim Acta) - "The modified AMGS metric will assist practicing analytical chemists in assessing the environmental impact of their separation methods from a single run in a given chromatographic mode. The proposed methodology identifies the minimum AMGS score corresponding to the greenest separation for routine chemical analysis."

Journal

Variation of harmful constituents in flavored hookah tobacco (ACS-Fall 2024) - "The levels of nicotine and minor tobacco alkaloids (nornicotine, anatabine and anabasine), as well as four TSNA (NNK, NNN, NAT, and NAB) were analyzed in these products using our established liquid chromatography-tandem mass spectrometry methods...Such differences in exposure have implications for addiction and cancer risks in users. There is a need for systematic assessment of hookah tobacco products and public education about the harms caused by hookah smoking."

CNS Disorders • Lung Cancer • Oncology • Psychiatry

The Gas Phase Protonation Sites of Six Naturally Occurring Nicotinoids. (PubMed, J Phys Chem Lett) - "The gas phase protonation sites of six naturally occurring nicotinoids, namely nicotine (NIC), nornicotine (NOR), anabasine (ANB), anatabine (ANT), cotinine (COT), and myosmine (MYO), consisting of a common Pyridine and differing non-Pyridine rings, have been determined for the first time at the physiological temperature from cryogenic ion trap infrared spectroscopy and electronic structure calculations...At room temperature, NIC is a mixture of Pyridine and Pyrrolidine (non-Pyridine) protomers, whereas NOR, ANB, ANT, and COT are pure Pyridine protomers and finally MYO is mostly a Pyroline (non-Pyridine) protomer. The nearly planar structure of MYO-H+, induced by the presence of a conjugated π system and confirmed from calculations and the UV absorption spectra, breaks from the trends observed for NIC, NOR, and ANB, since its structure is drastically different from the structures of the other nicotinoids."

Journal

High throughput and sensitive quantitation of tobacco-specific alkaloids and nitrosamines in wastewater. (PubMed, Talanta) - "Anabasine and anatabine were detected in all samples at concentrations of 5.0 - 33 ng/L and 12 - 41 ng/L, respectively...In-sewer stability of the nitrosamines was also assessed in this study, with four (NAT, NNAL, NNN, and N-nitrosoanabasine (NAB)) being stable (i.e. < 20 % transformation over 12 h in both control reactor (CR) and rising main reactor (RM) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) being moderately stable (< 40 % loss over 12 h in RM). This direct injection method provides a high-throughput approach in simultaneous investigation of tobacco use and assessment of public exposure to tobacco-specific nitrosamines."

Journal

Affinity of Nicotinoids to a Model Nicotinic Acetylcholine Receptor (nAChR) Binding Pocket in the Human Brain. (PubMed, J Phys Chem B) - "Using ab initio calculations for model binding pockets of increasing size composed of 3, 6, and 14 amino acids (3AA, 6AA, and 14AA) that are derived from the crystal structure, the differences in binding affinity of 6 nicotinoids, namely, nicotine (NIC), nornicotine (NOR), anabasine (ANB), anatabine (ANT), myosmine (MYO), and cotinine (COT) were correlated to their previously reported doses required for increases in intracranial self-stimulation (ICSS) thresholds, a metric for their addictive function...The larger pockets were found to model binding structures more accurately and predicted the addictive character of all nicotinoids, while smaller models, which are more computationally feasible, would only predict the addictive character of nicotinoids that are similar to nicotine. The present study identifies the binding affinity of the guest nicotinoid to the host binding pocket as a strong descriptor of the nicotinoid's addiction potential, and as such it can be..."

Journal • CNS Disorders • Nicotine Addiction • Psychiatry

New Pyridyl and Dihydroisoquinoline Alkaloids Isolated from the Chevron Nemertean Amphiporus angulatus. (PubMed, Mar Drugs) - "GTS-21, a drug candidate based on the anabaseine scaffold, has pro-cognitive and anti-inflammatory actions in animal models. One compound is an isomer of the tobacco alkaloid anatabine, another is a unique dihydroisoquinoline, and three are analogs of the tetrapyridyl nemertelline. The structural characteristics of these ten compounds suggest several possible pathways for their biosynthesis."

Journal

Reinforcing and adverse observable effects of nicotine and minor tobacco alkaloids in squirrel monkeys. (PubMed, Drug Alcohol Depend) - "In observation studies, all minor tobacco alkaloids produced adverse observable effects that were either comparable or more pronounced than nicotine. Collectively, the present results showing that nicotine and the minor tobacco alkaloids nornicotine, anatabine, and myosmine produce differential reinforcing and acute adverse observable effects in monkeys provides further evidence that these constituents may differently contribute to the psychopharmacological and adverse effects of tobacco consumption."

Journal • CNS Disorders • Movement Disorders • Psychiatry • Tobacco Addiction

Effects of a novel microbial fermentation medium produced by Tremella aurantialba SCT-F3 on cigar filler leaf. (PubMed, Front Microbiol) - "Methylpyrazine, D,L-anatabine, and β-nicotyrine were negatively correlated with Luteimonas, Mitochondria, Paracoccus, Stemphylium, and Stenotrophomonas. This research provides not only a new microbial fermentation medium that utilizes edible and medicinal fungi to improve the quality of fermented CFLs, but also new ideas for the development and application of other edible medicinal fungi to improve the quality of cigar tobacco leaves."

Journal

Nicotine-mediated effects in neuronal and mouse models of synucleinopathy. (PubMed, Front Neurosci) - "Moreover, when investigating the role of nicotinic acetylcholine receptor (nAChR) signaling in nicotine's neuroprotective effects in iPSC-derived dopaminergic neurons, we observed that while α4-specific antagonists reduced the nicotine-induced calcium response, α4 agonists (e.g., AZD1446 and anatabine) mediated similar neuroprotective responses against α-Syn PFF-provoked neurodegeneration. Our results show that nicotine attenuates α-Syn-provoked neuropathology in vivo and in a humanized neuronal model of synucleinopathy and that activation of α4β2 nicotinic receptors might mediate these neuroprotective effects."

Journal • Preclinical • CNS Disorders • Inflammation • Movement Disorders • Parkinson's Disease

Suppression of pyrrolidine ring biosynthesis and its effects on gene expression and subsequent accumulation of anatabine in leaves of tobacco (N. tabacum L.). (PubMed, BMC Genomics) - "Our results are the first concrete evidence that suppression of MPO leads to decreased nicotine in favor of anatabine in tobacco roots and that this anatabine is successfully transported to tobacco leaves. Alkaloid transport in plants remains to be investigated to higher detail due to high variation of its efficiency among Nicotiana species and varieties of tobacco. Our research adds important step to better understand pyrrolidine ring biosynthesis and its effects on gene expression and subsequent accumulation of anatabine."

Journal • Metabolic Disorders • MPO

Multiple Pharmacotherapy Adaptations for Smoking Cessation Based on Treatment Response in Black Adults Who Smoke: A Randomized Clinical Trial. (PubMed, JAMA Netw Open) - P3 | "The ADT group consisted of 196 individuals who received a nicotine patch (NP) and up to 2 pharmacotherapy adaptations, with a first switch to varenicline at week 2 and, if needed, a second switch to bupropion plus NP (bupropion + NP) based on carbon monoxide (CO)-verified smoking status (CO ≥6 ppm) at week 6...Anabasine-verified and anatabine-verified point-prevalence abstinence at week 12 (primary end point) and weeks 18 and 26 (secondary end points)...Those who achieved abstinence in the first 2 weeks of the study were significantly more likely to achieve later abstinence, highlighting early treatment response as an important area for preemptive intervention. ClinicalTrials.gov Identifier: NCT03897439."

Clinical • Journal • Tobacco Cessation

Current Status and De Novo Synthesis of Anti-Tumor Alkaloids in Nicotiana. (PubMed, Metabolites) - "Up to 4% of the total dry weight of Nicotiana was found to be composed of alkaloids, where nicotine, nornicotine, anatabine, and anabasine are reported as the dominant alkaloids. Additionally, among the alkaloids present in Nicotiana, β-carboline (Harmane and Norharmane) and Kynurenines are found to show anti-tumor effects, especially in the cases of colon and breast cancers. Creating new or shunting of existing biosynthesis pathways in different species of Nicotiana resulted in de novo or increased synthesis of different anti-tumor molecules or their derivatives or precursors including Taxadiane (~22.5 µg/g), Artemisinin (~120 μg/g), Parthenolide (~2.05 ng/g), Costunolide (~60 ng/g), Etoposide (~1 mg/g), Crocin (~400 µg/g), Catharanthine (~60 ng/g), Tabersonine (~10 ng/g), Strictosidine (~0.23 mg/g), etc. Enriching the precursor pool, especially Dimethylallyl Diphosphate (DMAPP), down-regulating other bi-product pathways, compartmentalization or metabolic..."

Journal • Review • Breast Cancer • Oncology • Solid Tumor

Improving Wastewater-Based Tobacco Use Estimates Using Anabasine. (PubMed, Environ Sci Technol) - "Recently, the minor tobacco alkaloids anabasine and anatabine have been suggested as more specific biomarkers for tobacco use since nicotine use can be from both tobacco and non-tobacco sources...Triangulation of tobacco sales data and tobacco use estimated from either anabasine or cotinine showed that anabasine-based estimates were 5% higher than sales data, while cotinine-based estimates were between 2 and 28% higher. Our results provided concrete evidence to confirm the suitability of anabasine as a specific biomarker for monitoring tobacco use by WBE."

Journal • Nicotine Addiction

Novel proposed cutoff values for anatabine and anabasine in differentiating smokers from non-smokers. (PubMed, Clin Biochem) - "The cutoff values >0.097 ng/mL for anatabine and >0.236 ng/mL for anabasine appear to better differentiate tobacco users from abstainers than the current reference threshold (>2 ng/mL for both alkaloids). It may considerably impact patients' care, especially in transplantation settings in which smoking abstinence is essential to avoid adverse outcomes of transplantation."

Journal • Nicotine Addiction • Tobacco Cessation • Transplantation

Tobacco Alkaloid Assessment in a DSS-Induced Colitis Mouse Model with a Fully Humanized Immune System. (PubMed, Int J Mol Sci) - "In the present study, we investigated the potential anti-inflammatory activities of the tobacco alkaloids nicotine and anatabine in a dextran sulfate sodium (DSS)-induced UC mouse model with a fully humanized immune system...Gene expression analysis in the context of biological network models of IBD further pinpointed a possible mechanism by which nicotine attenuated DSS-induced colitis in humanized mice. The current study enables further investigation of possible molecular mechanisms by which tobacco alkaloids attenuate UC symptoms."

Journal • Preclinical • Crohn's disease • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Nicotine Addiction • Ulcerative Colitis

Nicotine Exerts a Stronger Immunosuppressive Effect Than Its Structural Analogs and Regulates Experimental Colitis in Rats. (PubMed, Biomedicines) - "Nicotine, or a respective structural analog (nornicotine, cotinine, anabasine, myosmine, and anatabine), was administered intraperitoneally daily to rats (n = 6/group) exhibiting dextran sulfate sodium-induced experimental colitis...Moreover, the secretion of these cytokines was suppressed in lipopolysaccharide-stimulated rat macrophages (MΦ) treated with nicotine. In conclusion, nicotine better alleviates experimental UC than the examined structural analogs by activating nAChR7 expression and suppressing proinflammatory cytokines in MΦ."

Journal • Preclinical • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis • IL6

Simultaneous separation of nicotine and its relative alkaloids in electronic cigarettes using gas chromatography-mass spectrometry (GC-MS) and capillary electrophoresis (CE) (ACS-Sp 2023) - "Currently, there is no published data on the analysis of nicotine and related alkaloids in e-liquids using CE.This presentation would provide a new approach by simultaneously detecting eight alkaloids (nicotine, nornicotine, anabasine, cotinine, myosmine, anatabine, nicotine-N-oxide, and nicotine-cis-oxide) present in e-liquids using both GC-MS and CE.To this date, we have successfully optimized the GC-MS conditions for the separation of exploiting nicotine alkaloid standards by studying various segments of the temperature programming curve to optimize the separation...These conditions produced a well-resolved chromatogram of all eight peaks in the shortest time possible at 23 mins.Next, we will analyze the same eight nicotine alkaloids by CE with MS compatible volatile buffers. Finally, we will perform method validation for both GC-MS and CE and quantitate these alkaloids in synthetic tobacco-fee e-liquids vs naturally extracted tobacco e-liquids."

Systems biology reveals anatabine to be an NRF2 activator. (PubMed, Front Pharmacol) - "Using an appropriate luciferase reporter cell system, we were able to demonstrate that anatabine treatment results in NRF2 (nuclear factor-erythroid factor 2-related factor 2) translocation, and our systematic phosphoproteomic assays showed that anatabine treatment results in activation of MAPK signaling. While there are certain areas to be explored in deciphering the exact anti-inflammatory mechanisms of action of anatabine and other NRF2 activators, we believe that anatabine constitutes an interesting molecule for its therapeutic potential in NRF2-related diseases."

Journal • Alzheimer's Disease • CNS Disorders • Endocrine Disorders • Immunology • Inflammation • Multiple Sclerosis

Fractionation and Extraction Optimization of Potentially Valuable Compounds and Their Profiling in Six Varieties of Two Nicotiana Species. (PubMed, Molecules) - "Among the most interesting results, we found high variability of anatabine content between species and varieties, ranging from 287 to 1699 µg/g. In addition, we found that CGA (1305 µg/g) and rutin (7910 µg/g) content are orders of magnitude lower in the Burley variety as compared to all others."

Journal

Metabolomics and proteomics revealed the synthesis difference of aroma precursors in tobacco leaves at various growth stages. (PubMed, Plant Physiol Biochem) - "On the other hand, alkaloids such as nicotine, nornicotine, and anatabine increased continuously in tobacco leaves during the three growth stages. This study helps us understand the growth and development characteristics of Yun87 flue-cured tobacco in the field before harvest, and it provides a certain omics basis for the industrial crop flue-cured tobacco."

Journal

Accuracy improvement of determination of seven minor tobacco alkaloids in mainstream cigarette smoke using analyte protectants by gas chromatography-mass spectrometry. (PubMed, J Chromatogr A) - "This study investigates the compensation effects of novel analyte protectants (APs) for matrix effects (MEs) to determine seven minor tobacco alkaloids (nornicotine, myosmine, anabasine, anatabine, nicotyrine, 2,3'-bipyridine, and cotinine) in mainstream cigarette smoke with high accuracy and robustness...The results showed that the RSD values were higher (3.5-25.4%) without the AP combination than that (<6.7%) with the AP combination. Because of its high accuracy, precision, and robustness, this method has good practical prospects."

Journal

Biomarkers of Exposure and Potential Harm in Exclusive Users of Nicotine Pouches and Current, Former, and Never Smokers: Protocol for a Cross-sectional Clinical Study. (PubMed, JMIR Res Protoc) - "The results of this study will provide information on toxicant exposure and biomarkers associated with the development of smoking-related diseases among users of NPs compared with smokers, as well as on the potential role of NPs in THR."

Biomarker • Journal • Nicotine Addiction • ICAM1