Chain length dependence of the interactions of bisquaternary ligands with the Torpedo nicotinic acetylcholine receptor

Carter, Chris R.J.; Cao, Liren; Kawai, Hideki; Smith, Peter A.; Dryden, William F.; Raftery, Michael A.; Dunn, Susan M. J.

doi:10.1016/j.bcp.2006.10.011

Cited by 11 publications

(6 citation statements)

References 33 publications

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“…Meanwhile, different kinetics of the slow rates observed for the two semirigid agonists that structurally differ only at the position of the acetyl group (position 3 for arecolone-MeI versus position 4 for isoarecolone-MeI in the dihydropyridine ring) suggests that the agonist binding sites of nAChRs are highly sensitive to ligand structure for inducing different conformations of nAChR. This is consistent with the observations that the determinants of ligand recognition in the agonist binding sites are diverse and that specific recognition of various ligand structures by different amino acids determines ligand activity (11,40).…”

Section: Discussionsupporting

confidence: 82%

Kinetics of agonist-induced intrinsic fluorescence changes in the Torpedo acetylcholine receptor

Kawai¹,

Raftery²

2010

Journal of Biochemistry

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The nicotinic acetylcholine receptor from Torpedo electric organs is a ligand-gated ion channel that undergoes conformational transitions for activation and/or desensitization. Earlier work suggested that intrinsic fluorescence changes of the receptor monitors kinetic transitions toward the high-affinity, desensitized state. Here, using highly purified membrane preparations to minimize contaminating fluorescence, we examined kinetic mechanisms of the receptor as monitored by its intrinsic fluorescence. Fluorescence changes were specific to the receptor as they were blocked by alpha-bungarotoxin and were induced by agonists, but not by the antagonist hexamethonium. Acetylcholine, carbamylcholine and suberyldicholine showed only one kinetic phase with relatively fast rates (t(1/2) = 0.2-1.2 s). Effective dissociation constants were at least an order of magnitude higher than the high affinity, equilibrium binding constants for these agonists. A semirigid agonist isoarecolone-methiodide, whose activation constant was approximately 3-fold lower than acetylcholine, induced an additional slow phase (t(1/2) = 4.5-9 s) with apparent rates that increased and then decreased in a concentration dependent manner, revealing a branched mechanism for conformational transitions. We propose that the intrinsic fluorescence changes of the receptor describe a process(es) toward a fast desensitization state prior to the formation of the high affinity state.

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Section: Discussionsupporting

confidence: 82%

Kinetics of agonist-induced intrinsic fluorescence changes in the Torpedo acetylcholine receptor

Kawai¹,

Raftery²

2010

Journal of Biochemistry

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“…For example, whereas the bis-quaternary ligand hexamethonium, with the structure (CH3) 3 N + -(CH2) n -N + (CH3) 3 and n = 6, is an antagonist, decamethonium with n = 10 is a weak agonist. Similarly, the bis-choline ester succinylcholine, with the structure (CH3) 3 N + CH 2 CH 2 OCO-(CH2) n -COOCH 2 CH 2 N + (CH3) 3 and n = 2, is a weak, low-affinity agonist (succinylcholine), but suberyldicholine with n = 6 is a strong, high-affinity agonist (41). In suberyldicholine, the inter-quaternary distance of 18 Å is long enough so that with one end lodged in the aromatic pocket at the principal face, the other end can extend to the complementary face.…”

Section: Pharmacologymentioning

confidence: 99%

End-Plate Acetylcholine Receptor: Structure, Mechanism, Pharmacology, and Disease

Sine

2012

Physiological Reviews

117

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The synapse is a localized neurohumoral contact between a neuron and an effector cell and may be considered the quantum of fast intercellular communication. Analogously, the postsynaptic neurotransmitter receptor may be considered the quantum of fast chemical to electrical transduction. Our understanding of postsynaptic receptors began to develop about a hundred years ago with the demonstration that electrical stimulation of the vagus nerve released acetylcholine and slowed the heart beat. During the past 50 years, advances in understanding postsynaptic receptors increased at a rapid pace, owing largely to studies of the acetylcholine receptor (AChR) at the motor endplate. The endplate AChR belongs to a large superfamily of neurotransmitter receptors, called Cys-loop receptors, and has served as an exemplar receptor for probing fundamental structures and mechanisms that underlie fast synaptic transmission in the central and peripheral nervous systems. Recent studies provide an increasingly detailed picture of the structure of the AChR and the symphony of molecular motions that underpin its remarkably fast and efficient chemoelectrical transduction.

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“…4,5,[23][24][25][26] Divalent neonicotinoids may bind to the AChR recognition site with the one pharmacophore, and the another successively binds to the site at the tetherlength distance from the first, inducing a conformational change to modulate the channel. Elucidation of the binding mechanism of divalent neonicotinoids might contribute to clarify the interplay among the subsites within the insect nAChR by identifying the recognition sites at the tether length distance.…”

Section: )mentioning

confidence: 99%

Pharmacophore of neonicotinoid insecticides

Kagabu

2008

J. Pestic. Sci.

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Our recent study related to neonicotinoid pharmacophore was presented. The first topic described on the QSAR study with 17 variants of 2-nitroiminoimizolidine. The insect neuroblocking potency is proportionally related both to the Mulliken charge on the nitro oxygen atom and log P. The second raised the functional possibility of the 3-fluoropropyl group as an H-bond acceptor for the neonicotinoid skeleton. Its 2-nitroiminoimidazolidine derivative actually showed the insecticidal tendency common to the neonicotinoids bearing a 6-chloro-3-pyridylmethyl group, although the activating strength was not as high as expected. The third introduced a new type of neonicotinoid compounds of alkylene-tethered twin-structure. The insecticidal activity against American cockroaches was dependent on the tether length and maximized at the hexamethylene with the minimum lethal dose of 2.2 nmol/insects, comparable to that of imidacloprid.

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Chain length dependence of the interactions of bisquaternary ligands with the Torpedo nicotinic acetylcholine receptor

Cited by 11 publications

References 33 publications

Kinetics of agonist-induced intrinsic fluorescence changes in the Torpedo acetylcholine receptor

Kinetics of agonist-induced intrinsic fluorescence changes in the Torpedo acetylcholine receptor

End-Plate Acetylcholine Receptor: Structure, Mechanism, Pharmacology, and Disease

Pharmacophore of neonicotinoid insecticides

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