Nicotinic Agonists, Antagonists, and Modulators From Natural Sources

Daly, John W.

doi:10.1007/s10571-005-3968-4

Cited by 181 publications

(147 citation statements)

References 207 publications

(246 reference statements)

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“…39) The term aimed at differentiating these new insecticides based on their unique structural and pharmacophoric features compared to the nicotinoids (a term also suggested by Yamamoto back in the 1960s) 40) which are likewise nAChR orthosteric modulators yet containing a key basic nitrogen and structurally related to nicotine (for instance epibatidine, cytisine, anatoxin). 41) Imidacloprid was actually not discovered from natural alkaloids but from synthetic nitromethylene heterocycles (Fig. 4).…”

Section: Nachr Orthosteric Modulatorsmentioning

confidence: 99%

The invertebrate pharmacology of insecticides acting at nicotinic acetylcholine receptors

Crossthwaite

Bigot

Camblin

et al. 2017

Journal of Pesticide Science

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The nicotinic acetylcholine receptor (nAChR) is a ligand-gated ion channel composed of 5 protein subunits arranged around a central cation selective pore. Several classes of natural and synthetic insecticides mediate their effect through interacting at nAChRs. This review examines the basic pharmacology of the neonicotinoids and related chemistry, with an emphasis on sapfeeding insects from the order Hemiptera, the principle pest target for such insecticides. Although the receptor subunit stoichiometry for endogenous invertebrate nAChRs is unknown, there is clear evidence for the existence of distinct neonicotinoid binding sites in native insect preparations, which reflects the predicted wide repertoire of nAChRs and differing pharmacology within this insecticide class. The spinosyns are principally used to control chewing pests such as Lepidoptera, whilst nereistoxin analogues are used on pests of rice and vegetables through contact and systemic action, the pharmacology of both these insecticides is unique and different to that of the neonicotinoids.

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Section: Nachr Orthosteric Modulatorsmentioning

confidence: 99%

The invertebrate pharmacology of insecticides acting at nicotinic acetylcholine receptors

Crossthwaite

Bigot

Camblin

et al. 2017

Journal of Pesticide Science

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“…[25][26][27] It is surprising that the lobeline structure is predicted as clearly agonist-bound, and we therefore proceeded to investigate the 2BYS structure using MD simulation. As described in the Materials and Methods section, we launched an MD simulation of the 2BYS structure with lobeline bound.…”

Section: Evaluation Of Crystal Structures Containing Ligands Of Unclementioning

confidence: 99%

Enhanced meta‐analysis of acetylcholine binding protein structures reveals conformational signatures of agonism in nicotinic receptors

Stober

Abrams

2012

Protein Science

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The soluble acetylcholine binding protein (AChBP) is the default structural proxy for pentameric ligand-gated ion channels (LGICs). Unfortunately, it is difficult to recognize conformational signatures of LGIC agonism and antagonism within the large set of AChBP crystal structures in both apo and ligand-bound states, primarily because AChBP conformations in this set are nearly superimposable (root mean square deviation < 1.5 Å ). We have undertaken a systematic, alignment-free approach to elucidate conformational differences displayed by AChBP that cleanly differentiate apo/antagonist-bound from agonist-bound states. Our approach uses statistical inference based on both crystallographic states and conformations sampled during long molecular dynamics simulations to select important inter-C a distances and map their collective values onto functional states. We observe that binding of (nAChR) agonists to AChBP elicits clockwise rotation of the inner b-sheet with respect to the outer b-sheet, causing tilting of the cys-loop away from the five-fold axis, in a manner quite similar to that speculated for a-subunits of the heteromeric nAChR structure (Unwin, J Mol Biol 2005;346:967), making this motion potentially important in transmission of the gating signal to the transmembrane domain of a LGIC. The method is also successful at discriminating partial from full agonists and supports the hypothesis that a particularly controversial ligand, lobeline, is in fact an LGIC antagonist.

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“…It is estimated that more than 4,000 compounds are present in tobacco leaves and tobacco smoke [22]. While the pharmacological activity of the majority of these compounds have not been identified, several commercially available alkaloid components of tobacco smoke have been structurally characterized [22] and their binding affinities to nAChRs established [23][24][25]. Thus, tobacco smoke represents a complex mixture containing pharmacologically active components, which can be used as a model for the "missing peak" chromatographic screening of medicinally active biological and chemical mixtures.…”

Section: Introductionmentioning

confidence: 99%

Screening of tobacco smoke condensate for nicotinic acetylcholine receptor ligands using cellular membrane affinity chromatography columns and missing peak chromatography

Maciuk

Moaddel

Haginaka

et al. 2008

Journal of Pharmaceutical and Biomedical Analysis

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This manuscript reports an approach to the screening of natural product extracts for compounds which are active at membrane-bound receptors, ion channels and transporters. The technique is based upon cellular membrane affinity chromatography (CMAC) columns created through the immobilization of cellular membrane fragments on liquid chromatography stationary phases. In this study a CMAC (nAChR(+)) column was created out of membranes from a transfected cell line expressing the α 3 β 4 neuronal nicotinic acetylcholine receptor (nAChR) and the column was used to screen tobacco smoke condensates. A strategy involving parallel screening with a CMAC column created from a non-transfected form of the same cell line, CMAC(nAChR(−)) was adopted. The condensate was chromatographed on both columns, timed fractions collected and concentrated. Each fraction was analyzed on a C 18 column in order to establish a chromatographic fingerprint of each fraction and a differential elution profile of each compound. Comparison of the elution profiles from the CMAC (nAChR(+)) and CMAC(nAChR(−)) columns identified patterns that could be associated with high affinity ligands and with low-affinity/non-binding compounds. Known strong ligands ((S)-Nicotine, (R,S)-Anatabine, N'-Nitrosonornicotine), weak ligands ((R,S)-Nornicotine, Anabasine) as well as known non-ligands (N-Methyl-γ-oxo-3-pyridinebutanamide, (1'S,2′S)-Nicotine 1'-oxide) have been identified in the complex extract. The results demonstrate that CMAC-based screens can be used in the identification of compounds within natural product extracts that bind to membrane-based targets.

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Nicotinic Agonists, Antagonists, and Modulators From Natural Sources

Cited by 181 publications

References 207 publications

The invertebrate pharmacology of insecticides acting at nicotinic acetylcholine receptors

The invertebrate pharmacology of insecticides acting at nicotinic acetylcholine receptors

Enhanced meta‐analysis of acetylcholine binding protein structures reveals conformational signatures of agonism in nicotinic receptors

Screening of tobacco smoke condensate for nicotinic acetylcholine receptor ligands using cellular membrane affinity chromatography columns and missing peak chromatography

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