Structural Studies of Nicotinoids: Cotinine versus Nicotine

Uriarte, Iciar; Pérez, Cristóbal; Caballero-Mancebo, Elena; Basterretxea, Francisco J.; Lesarri, Alberto; Fernández, José A.; Cocinero, Emilio J.

doi:10.1002/chem.201700023

Cited by 10 publications

(11 citation statements)

References 28 publications

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“…The experimental results have been extended to 17 additional isotopic species arising from single and double heavy atom substitution ( 13 C and 15 N isotopologues) observed thanks to the high sensitivity of our CP‐FTMW experimental set‐up and 15 N2 indazole enriched sample. A total of over 1600 rotational transitions were measured for the 18 studied isotopic species.…”

Section: Resultsmentioning

confidence: 99%

“…The structural determination of indazole in the gas phase was carried out by using rotational spectroscopy in combination with supersonic expansion. In particular, we used the Chirped Pulse Fourier Transform Microwave (CP‐FTMW) spectrometer available at the University of the Basque Country UPV/EHU and fully described elsewhere . It is based on the Pate group′s original design and allows for the acquisition of the rotational spectrum in the 6–18 GHz frequency range in a single molecular pulse.…”

Section: Methodsmentioning

confidence: 99%

“…Gas to the high sensitivity of our CP-FTMW experimental set-up [74] and 15 N2 indazole enriched sample. At otal of over 1600 rotational transitions were measured for the 18 studied isotopic species.…”

Section: Compoundmentioning

confidence: 99%

“…In particular,w eu sed the Chirped Pulse Fourier Transform Microwave (CP-FTMW) spectrometer available at the University of the Basque Country UPV/EHU and fully described elsewhere. [74] It is based on the Pate group'so riginal design [22] and allows for the acquisition of the rotational spectrum in the 6-18 GHz frequency range in as ingle molecular pulse. Moreover,i ti s possible to average over time to increase the signal-to-noise ratio.…”

Section: Experimental Mw Determinationmentioning

confidence: 99%

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Bond Length Alternation Observed Experimentally: The Case of 1H‐Indazole

Uriarte

Reviriego

Calabrese

et al. 2019

Chemistry A European J

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Bond length alternation is a chemical phenomenon in benzene rings fused to other rings, which has been mainly predicted theoretically. Its physical origin is still not clear and has generated discussion. Here, by using a strategy that combines microwave spectroscopy, custom‐made synthesis and high‐level ab initio calculations, we demonstrate that this phenomenon is clearly observed in the prototype indazole molecule isolated in the gas phase. The 1H‐indazole conformer was detected by rotational spectroscopy, and its 17 isotopologues resulting from single and double heavy atom substitution (13C and 15N) were also unambiguously observed. Several experimental structures were determined and, in particular, the most useful semi‐experimental equilibrium structure (reSE), allowed determination of the heavy atom bond lengths to milli‐Ångstrom precision. The experimentally determined bond length alternation is estimated to correspond to 60:40 contributions from the two resonant forms of 1H‐indazole.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Compoundmentioning

confidence: 99%

Section: Experimental Mw Determinationmentioning

confidence: 99%

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Bond Length Alternation Observed Experimentally: The Case of 1H‐Indazole

Uriarte

Reviriego

Calabrese

et al. 2019

Chemistry A European J

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“…Nicotine and cotinine are classic agonists of nAChRs, 22 among which a7 nAChR and a4b2 nAChR are the evolutionarily oldest nAChRs and…”

Section: Report Llmentioning

confidence: 99%

Nicotine and its metabolite cotinine target MD2 and inhibit TLR4 signaling

Peng

Lin

et al. 2021

The Innovation

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Nicotine is the principal alkaloid of tobacco often manufactured into cigarettes and belongs to a highly addictive class of drugs. Nicotine attenuates the neuroinflammation induced by microglial activation. However, the molecular target(s) underlying anti-inflammatory action of nicotine has not been fully understood. Considering the psychoactive substances morphine, cocaine, and methamphetamine act as xenobiotic-associated molecular patterns and can be specifically sensed by the innate immune receptor Toll-like receptor 4 (TLR4), here we sought to delineate whether nicotine and/or its metabolite cotinine may be recognized by the innate immune system via myeloid differentiation protein 2 (MD2), an accessory protein of TLR4 that is responsible for ligand recognition. MD2intrinsic fluorescence titrations, surface plasmon resonance, and competitive displacement binding assays with curcumin (MD2 probe) demonstrated that both nicotine and cotinine targeted the lipopolysaccharide (LPS; TLR4 agonist) binding pocket of MD2 with similar affinities. The cellular thermal shift assay indicated that nicotine binding increased, while cotinine binding decreased, MD2 stability. These biophysical binding results were further supported by in silico simulations. In keeping with targeting MD2, both nicotine and cotinine inhibited LPS-induced production of nitric oxide and tumor necrosis factor alpha (TNF-a) and blocked microglial activation. Neither a pan nicotinic acetylcholine receptor (nAChR) inhibitor nor RNAi for nAChRs abolished the suppressive effect of nicotine-and cotinine-induced neuroinflammation. These data indicate that TLR4 inhibition by nicotine and cotinine at the concentrations tested in BV-2 cells is independent of classic neuronal nAChRs and validate that MD2 is a direct target of nicotine and cotinine in the inhibition of innate immunity.

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