Genomes and Genes
Summary: Drugs that bind to nicotinic cholinergic receptors (RECEPTORS, NICOTINIC) and block the actions of acetylcholine or cholinergic agonists. Nicotinic antagonists block synaptic transmission at autonomic ganglia, the skeletal neuromuscular junction, and at central nervous system nicotinic synapses.
- Ortiz N, O Neill H, Marks M, Grady S. Varenicline blocks ?2*-nAChR-mediated response and activates ?4*-nAChR-mediated responses in mice in vivo. Nicotine Tob Res. 2012;14:711-9 pubmed publisher..Varenicline acts as a functional antagonist of ?2*-nAChRs, blocking certain effects of nicotine. At higher doses, varenicline is an agonist of ?4*-nAChRs producing physiological changes in mice. ..
- Muttenthaler M, Akondi K, Alewood P. Structure-activity studies on alpha-conotoxins. Curr Pharm Des. 2011;17:4226-41 pubmed..Additionally, their synthesis, chemical modifications, the development of more selective and stable analogues and their therapeutic potential are discussed. ..
- Luo S, Zhangsun D, Zhu X, Wu Y, Hu Y, Christensen S, et al. Characterization of a novel ?-conotoxin TxID from Conus textile that potently blocks rat ?3?4 nicotinic acetylcholine receptors. J Med Chem. 2013;56:9655-63 pubmed publisher..CTx TxID is a novel tool with which to probe the structure and function of ?3?4 nAChRs. ..
- Gotti C, Guiducci S, Tedesco V, Corbioli S, Zanetti L, Moretti M, et al. Nicotinic acetylcholine receptors in the mesolimbic pathway: primary role of ventral tegmental area alpha6beta2* receptors in mediating systemic nicotine effects on dopamine release, locomotion, and reinforcement. J Neurosci. 2010;30:5311-25 pubmed publisher
- Grady S, Drenan R, Breining S, Yohannes D, Wageman C, Fedorov N, et al. Structural differences determine the relative selectivity of nicotinic compounds for native alpha 4 beta 2*-, alpha 6 beta 2*-, alpha 3 beta 4*- and alpha 7-nicotine acetylcholine receptors. Neuropharmacology. 2010;58:1054-66 pubmed publisher..This approach has identified several compounds with agonist or partial agonist activity that display improved selectivity for alpha 6 beta 2*-nAChR. ..
- Glick S, Sell E, McCallum S, Maisonneuve I. Brain regions mediating ?3?4 nicotinic antagonist effects of 18-MC on nicotine self-administration. Eur J Pharmacol. 2011;669:71-5 pubmed publisher..The data also suggest that an action of 18-MC in the interpeduncular nucleus may attenuate aversive and/or depressive effects of nicotine. ..
- Zheng G, Zhang Z, Dowell C, Wala E, Dwoskin L, Holtman J, et al. Discovery of non-peptide, small molecule antagonists of ?9?10 nicotinic acetylcholine receptors as novel analgesics for the treatment of neuropathic and tonic inflammatory pain. Bioorg Med Chem Lett. 2011;21:2476-9 pubmed publisher..These analogs represent a new class of analgesic for the treatment of neuropathic and tonic inflammatory pain. ..
- Yang K, Buhlman L, Khan G, Nichols R, Jin G, McIntosh J, et al. Functional nicotinic acetylcholine receptors containing ?6 subunits are on GABAergic neuronal boutons adherent to ventral tegmental area dopamine neurons. J Neurosci. 2011;31:2537-48 pubmed publisher..These presynaptic ?6?2*-nAChRs likely play important roles in nicotinic modulation of DA neuronal activity. ..
- Favreau P, Benoit E, Hocking H, Carlier L, D hoedt D, Leipold E, et al. A novel µ-conopeptide, CnIIIC, exerts potent and preferential inhibition of NaV1.2/1.4 channels and blocks neuronal nicotinic acetylcholine receptors. Br J Pharmacol. 2012;166:1654-68 pubmed publisher..We characterized the pharmacology of a new µ-conopeptide (µ-CnIIIC) on a range of preparations and molecular targets to assess its potential as a myorelaxant...
- Papke R, Wecker L, Stitzel J. Activation and inhibition of mouse muscle and neuronal nicotinic acetylcholine receptors expressed in Xenopus oocytes. J Pharmacol Exp Ther. 2010;333:501-18 pubmed publisher..Hexamethonium was a relatively nonselective antagonist with mixed competitive and noncompetitive activity...
- Luo S, Akondi K, Zhangsun D, Wu Y, Zhu X, Hu Y, et al. Atypical alpha-conotoxin LtIA from Conus litteratus targets a novel microsite of the alpha3beta2 nicotinic receptor. J Biol Chem. 2010;285:12355-66 pubmed publisher..The K79A mutant disrupted LtIA binding but was without effect on an LtIA analog where the Ser-Xaa-Pro motif is present, consistent with distinct binding modes. ..
- Muttenthaler M, Nevin S, Grishin A, Ngo S, Choy P, Daly N, et al. Solving the alpha-conotoxin folding problem: efficient selenium-directed on-resin generation of more potent and stable nicotinic acetylcholine receptor antagonists. J Am Chem Soc. 2010;132:3514-22 pubmed publisher..Together, these results underpin the development of more stable and potent nicotinic antagonists suitable for new drug therapies, and highlight the application of selenocysteine technology more broadly ..
- Dickson S, Hrabovszky E, Hansson C, Jerlhag E, Alvarez Crespo M, Skibicka K, et al. Blockade of central nicotine acetylcholine receptor signaling attenuate ghrelin-induced food intake in rodents. Neuroscience. 2010;171:1180-6 pubmed publisher..p. decreased the ability of palatable food to condition a place preference. These data suggest that ghrelin-induced food intake is partly mediated via nAChRs and that nicotinic blockade decreases the rewarding properties of food. ..
- Haydar S, Dunlop J. Neuronal nicotinic acetylcholine receptors - targets for the development of drugs to treat cognitive impairment associated with schizophrenia and Alzheimer's disease. Curr Top Med Chem. 2010;10:144-52 pubmed
- Ondachi P, Castro A, Luetje C, Damaj M, Mascarella S, Navarro H, et al. Synthesis and nicotinic acetylcholine receptor in vitro and in vivo pharmacological properties of 2'-fluoro-3'-(substituted phenyl)deschloroepibatidine analogues of 2'-fluoro-3'-(4-nitrophenyl)deschloroepibatidine. J Med Chem. 2012;55:6512-22 pubmed publisher
- Li Y, LaCroix C, Freeling J. Cytisine induces autonomic cardiovascular responses via activations of different nicotinic receptors. Auton Neurosci. 2010;154:14-9 pubmed publisher..Specifically, activations of alpha7 and alpha4beta2 nicotinic receptors are involved in cytisine-induced cardiovascular sympathetic and parasympathetic responses, respectively. ..
- Zanetti L, Picciotto M, Zoli M. Differential effects of nicotinic antagonists perfused into the nucleus accumbens or the ventral tegmental area on cocaine-induced dopamine release in the nucleus accumbens of mice. Psychopharmacology (Berl). 2007;190:189-99 pubmed..This suggests that multiple cholinergic/nicotinic pathways influence the effects of cocaine on mesolimbic DA neurons in complex, and sometimes opposing, patterns. ..
- Dwoskin L, Smith A, Wooters T, Zhang Z, Crooks P, Bardo M. Nicotinic receptor-based therapeutics and candidates for smoking cessation. Biochem Pharmacol. 2009;78:732-43 pubmed publisher..This review summarizes the currently available smoking cessation therapies and discusses emerging potential therapeutic approaches employing pharmacological agents which act as antagonists at nicotinic receptors. ..
- Papke R, Dwoskin L, Crooks P, Zheng G, Zhang Z, McIntosh J, et al. Extending the analysis of nicotinic receptor antagonists with the study of alpha6 nicotinic receptor subunit chimeras. Neuropharmacology. 2008;54:1189-200 pubmed publisher..Our data extend the information available on prototypical nAChR antagonists, and establish the alpha4/6 chimera as a useful new tool for screening drugs as selective nAChR antagonists. ..
- Millard E, Nevin S, Loughnan M, Nicke A, Clark R, Alewood P, et al. Inhibition of neuronal nicotinic acetylcholine receptor subtypes by alpha-Conotoxin GID and analogues. J Biol Chem. 2009;284:4944-51 pubmed publisher..Overall, our findings contribute to the understanding of the structure-activity relationships of alpha-conotoxins and may be beneficial for the ongoing attempts to exploit modulators of the neuronal nAChRs as therapeutic agents. ..
- Romanelli M, Gratteri P, Guandalini L, Martini E, Bonaccini C, Gualtieri F. Central nicotinic receptors: structure, function, ligands, and therapeutic potential. ChemMedChem. 2007;2:746-67 pubmed
- Whiteaker P, Christensen S, Yoshikami D, Dowell C, Watkins M, Gulyas J, et al. Discovery, synthesis, and structure activity of a highly selective alpha7 nicotinic acetylcholine receptor antagonist. Biochemistry. 2007;46:6628-38 pubmed..The peptide was also shown to be highly selective in competition binding assays in rat brain membranes. alpha-CtxArIB[V11L,V16D] is the most selective ligand yet reported for alpha7 nAChRs. ..
- Ulens C, Akdemir A, Jongejan A, van Elk R, Bertrand S, Perrakis A, et al. Use of acetylcholine binding protein in the search for novel alpha7 nicotinic receptor ligands. In silico docking, pharmacological screening, and X-ray analysis. J Med Chem. 2009;52:2372-83 pubmed publisher..The analysis of the dual binding mode of these dibenzosuberyl-containing compounds can lead to better understanding of the complex mode of action of similar tricyclic ligands on Cys-loop receptors. ..
- Lopez Vera E, Jacobsen R, Ellison M, Olivera B, Teichert R. A novel alpha conotoxin (alpha-PIB) isolated from C. purpurascens is selective for skeletal muscle nicotinic acetylcholine receptors. Toxicon. 2007;49:1193-9 pubmed..Testing of alpha-PIB against other receptors indicated that the inhibitory effect is specific for skeletal muscle nAChRs. alpha-PIB shares the key biochemical and pharmacological characteristics of the alpha-conotoxin family. ..
- Hashimoto K, Ishima T, Fujita Y, Matsuo M, Kobashi T, Takahagi M, et al. Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of the novel selective alpha7 nicotinic receptor agonist SSR180711. Biol Psychiatry. 2008;63:92-7 pubmed..Therefore, alpha7 nAChR agonists including SSR180711 are potential therapeutic drugs for treating cognitive deficits in schizophrenic patients. ..
- Khwaja M, McCormack A, McIntosh J, Di Monte D, Quik M. Nicotine partially protects against paraquat-induced nigrostriatal damage in mice; link to alpha6beta2* nAChRs. J Neurochem. 2007;100:180-90 pubmed..Moreover, these data support epidemiological findings that environmental influences can elicit opposing effects on nigrostriatal dopaminergic integrity. ..
- Livett B, Sandall D, Keays D, Down J, Gayler K, Satkunanathan N, et al. Therapeutic applications of conotoxins that target the neuronal nicotinic acetylcholine receptor. Toxicon. 2006;48:810-29 pubmed..Brain. Res. 1059, 149-158]. ACV1 may act as an analgesic by decreasing ectopic excitation in sensory nerves. In addition ACV1 appears to accelerate the recovery of injured nerves and tissues. ..
- Rabenstein R, Caldarone B, Picciotto M. The nicotinic antagonist mecamylamine has antidepressant-like effects in wild-type but not beta2- or alpha7-nicotinic acetylcholine receptor subunit knockout mice. Psychopharmacology (Berl). 2006;189:395-401 pubmed..Therefore, compounds that decrease nAChR activity may be attractive new candidates for development as antidepressants in humans. ..
- Loughnan M, Nicke A, Lawrence N, Lewis R. Novel alpha D-conopeptides and their precursors identified by cDNA cloning define the D-conotoxin superfamily. Biochemistry. 2009;48:3717-29 pubmed publisher..mustelinus venom. The discovery of the precursors and several novel conotoxins from different species defines this large conotoxin family and expands our understanding of sequence diversification mechanisms in Conus species. ..
- Dineley K. Beta-amyloid peptide--nicotinic acetylcholine receptor interaction: the two faces of health and disease. Front Biosci. 2007;12:5030-8 pubmed..This review will discuss the extant literature on the subject in terms of clarifying this apparent dichotomy regarding the consequences of Abeta-nAChR interaction during health and disease. ..
- Wu J, Khan G, Nichols R. Dopamine release in prefrontal cortex in response to beta-amyloid activation of alpha7 * nicotinic receptors. Brain Res. 2007;1182:82-9 pubmed..These results suggest that Abeta alters dopamine release in mouse prefrontal cortex, perhaps involving distinct targets as it accumulates during Alzheimer's disease and leading to disruption of synaptic signaling. ..
- Peng C, Han Y, Sanders T, Chew G, Liu J, Hawrot E, et al. alpha4/7-conotoxin Lp1.1 is a novel antagonist of neuronal nicotinic acetylcholine receptors. Peptides. 2008;29:1700-7 pubmed publisher..Comparing the distinct primary structure with other functionally related alpha-conotoxins could indicate structural features in Lp1.1 that may be associated with its unique receptor recognition profile. ..
- Herrero J, Roberts M, Delicato L, Gieselmann M, Dayan P, Thiele A. Acetylcholine contributes through muscarinic receptors to attentional modulation in V1. Nature. 2008;454:1110-4 pubmed publisher..These results demonstrate that muscarinic cholinergic mechanisms play a central part in mediating the effects of attention in V1. ..
- D hoedt D, Bertrand D. Nicotinic acetylcholine receptors: an overview on drug discovery. Expert Opin Ther Targets. 2009;13:395-411 pubmed..Long-standing efforts in this field should soon result in the finding of new molecules that might be applicable to situations ranging from neurological diseases to immune treatments. ..
- Good C, Bay K, Buchanan R, Skinner R, Garcia Rill E. Muscarinic and nicotinic responses in the developing pedunculopontine nucleus (PPN). Brain Res. 2007;1129:147-55 pubmed..We conclude that, while the nicotinic inputs to the PPN may help modulate the developmental decrease in REM sleep, the muscarinic inputs appear to modulate different types of cells differentially. ..
- Liu Z, Neff R, Berg D. Sequential interplay of nicotinic and GABAergic signaling guides neuronal development. Science. 2006;314:1610-3 pubmed..Synergistic with nicotinic excitation, GABAergic inhibition constrains neuronal morphology and innervation. The results reveal a multitiered activity-dependent strategy controlling neuronal development. ..
- Park H, Lee P, Ahn Y, Choi Y, Lee G, Lee D, et al. Neuroprotective effect of nicotine on dopaminergic neurons by anti-inflammatory action. Eur J Neurosci. 2007;26:79-89 pubmed..Along with various neuroprotective effects of nicotine, the anti-inflammatory mechanism of nicotine could have a major therapeutic implication in the preventive treatment of PD. ..
- Gallego D, Gil V, Aleu J, Aulí M, Clave P, Jiménez M. Purinergic and nitrergic junction potential in the human colon. Am J Physiol Gastrointest Liver Physiol. 2008;295:G522-33 pubmed publisher..These differences might be responsible for complementary mechanisms of relaxation being phasic (ATP) and tonic (NO). ..
- McIntosh J, Absalom N, Chebib M, Elgoyhen A, Vincler M. Alpha9 nicotinic acetylcholine receptors and the treatment of pain. Biochem Pharmacol. 2009;78:693-702 pubmed publisher..1 binding to or action on cloned GABA-B receptors expressed in HEK cells or Xenopus oocytes. We review the background, findings and implications of use of compounds that act on alpha9* nAChRs.(1). ..
- Lopez Vera E, Aguilar M, Schiavon E, Marinzi C, Ortiz E, Restano Cassulini R, et al. Novel alpha-conotoxins from Conus spurius and the alpha-conotoxin EI share high-affinity potentiation and low-affinity inhibition of nicotinic acetylcholine receptors. FEBS J. 2007;274:3972-85 pubmed..Their unique properties make them excellent tools for studying the toxin-receptor interaction, as well as models with which to design highly specific therapeutic drugs. ..
- Whiteaker P, Marks M, Christensen S, Dowell C, Collins A, McIntosh J. Synthesis and characterization of 125I-alpha-conotoxin ArIB[V11L;V16A], a selective alpha7 nicotinic acetylcholine receptor antagonist. J Pharmacol Exp Ther. 2008;325:910-9 pubmed publisher..Furthermore, true equilibrium binding experiments could be performed on alpha7 nAChRs, something that is impossible with 125I-alpha-bungarotoxin. ..
- Ellison M, Feng Z, Park A, Zhang X, Olivera B, McIntosh J, et al. Alpha-RgIA, a novel conotoxin that blocks the alpha9alpha10 nAChR: structure and identification of key receptor-binding residues. J Mol Biol. 2008;377:1216-27 pubmed publisher..Our findings contribute to a better understanding of the molecular basis for antagonism of the alpha9alpha10 nAChR subtype, which is a target for the development of analgesics for the treatment of chronic neuropathic pain. ..
- Lluisma A, Lopez Vera E, Bulaj G, Watkins M, Olivera B. Characterization of a novel psi-conotoxin from Conus parius Reeve. Toxicon. 2008;51:174-80 pubmed..purpurascens belongs, suggests that greater structural and functional diversity of psi-conotoxins remains to be discovered from the members of this subgenus. ..
- Yoshimura R, Hogenkamp D, Li W, Tran M, Belluzzi J, Whittemore E, et al. Negative allosteric modulation of nicotinic acetylcholine receptors blocks nicotine self-administration in rats. J Pharmacol Exp Ther. 2007;323:907-15 pubmed..UCI-30002 represents validation of the concept that negative allosteric modulators may have significant benefits as a strategy for treating nicotine addiction and encourages the development of subtype-selective modulators. ..
- Jackson K, McIntosh J, Brunzell D, Sanjakdar S, Damaj M. The role of alpha6-containing nicotinic acetylcholine receptors in nicotine reward and withdrawal. J Pharmacol Exp Ther. 2009;331:547-54 pubmed publisher..These results suggest a role for the alpha6 nAChR subunit in nicotine reward and affective nicotine withdrawal but not acute nicotine-induced or physical withdrawal behaviors. ..
- Di Matteo V, Pierucci M, Di Giovanni G, Benigno A, Esposito E. The neurobiological bases for the pharmacotherapy of nicotine addiction. Curr Pharm Des. 2007;13:1269-84 pubmed..In this paper, the neurobiological mechanisms underlying nicotine addiction will be reviewed, and the possible strategies for new pharmacological treatments of nicotine dependence will be examined. ..
- Vincler M, McIntosh J. Targeting the alpha9alpha10 nicotinic acetylcholine receptor to treat severe pain. Expert Opin Ther Targets. 2007;11:891-7 pubmed..Although the exact mechanism of action is unknown, antagonism of the alpha9alpha10 nAChRs reduces the number of immune cells present at the site of injury. ..
- Löf E, Olausson P, deBejczy A, Stomberg R, McIntosh J, Taylor J, et al. Nicotinic acetylcholine receptors in the ventral tegmental area mediate the dopamine activating and reinforcing properties of ethanol cues. Psychopharmacology (Berl). 2007;195:333-43 pubmed..Pharmacological manipulations of selective nAChRs may thus be possible treatment strategies to prevent cue-induced relapse. ..
- Jerlhag E, Egecioglu E, Dickson S, Svensson L, ENGEL J. Alpha-conotoxin MII-sensitive nicotinic acetylcholine receptors are involved in mediating the ghrelin-induced locomotor stimulation and dopamine overflow in nucleus accumbens. Eur Neuropsychopharmacol. 2008;18:508-18 pubmed publisher..We therefore suggest that the alpha(3)beta(2), beta(3) and/or alpha(6) subtypes might be pharmacological targets for treatment of addictive behaviours including compulsive overeating and alcoholism. ..
- Li Y, LaCroix C, Freeling J. Specific subtypes of nicotinic cholinergic receptors involved in sympathetic and parasympathetic cardiovascular responses. Neurosci Lett. 2009;462:20-3 pubmed publisher..These data suggest that specific subtypes of nicotinic receptors at the level of the ganglia may play distinct roles in mediating sympathetic or parasympathetic activation. ..
- Bencan Z, Levin E. The role of alpha7 and alpha4beta2 nicotinic receptors in the nicotine-induced anxiolytic effect in zebrafish. Physiol Behav. 2008;95:408-12 pubmed publisher..This nicotine-induced anxiolytic effect was reversed by both MLA and DHbetaE, indicating that both nicotinic alpha7 and alpha4beta2 receptors are involved in the nicotinic effect on anxiety in zebrafish. ..
- Natividad L, Tejeda H, Torres O, O Dell L. Nicotine withdrawal produces a decrease in extracellular levels of dopamine in the nucleus accumbens that is lower in adolescent versus adult male rats. Synapse. 2010;64:136-45 pubmed publisher..Specifically, they suggest that GABA systems are underdeveloped during adolescence and this reduced inhibition of dopamine neurons in the VTA may lead to reduced decreases in NAcc dopamine of young animals experiencing withdrawal. ..
- Yang K, Hu J, Lucero L, Liu Q, Zheng C, Zhen X, et al. Distinctive nicotinic acetylcholine receptor functional phenotypes of rat ventral tegmental area dopaminergic neurons. J Physiol. 2009;587:345-61 pubmed publisher..Interestingly, each DAergic neuron predominantly expresses only one particularly functional nAChR subtype, which may have distinct but important roles in regulation of VTA DA neuronal function, DA transmission and nicotine dependence. ..
- Liu X, Palmatier M, Caggiula A, Donny E, Sved A. Reinforcement enhancing effect of nicotine and its attenuation by nicotinic antagonists in rats. Psychopharmacology (Berl). 2007;194:463-73 pubmed..These results demonstrate dose dependency of the reinforcement-enhancing effect of nicotine and suggest that activation of the alpha4beta2- but not alpha7-containing nAChRs may mediate this effect. ..
- Wildeboer K, Stevens K. Stimulation of the alpha4beta2 nicotinic receptor by 5-I A-85380 improves auditory gating in DBA/2 mice. Brain Res. 2008;1224:29-36 pubmed publisher..Thus, the present study implicates the involvement of more than one subtype of nAChR in the auditory gating of DBA/2 mice, specifically the alpha4beta2 nAChR, and its role in the response amplitude to the first stimulus. ..
- Salas R, Sturm R, Boulter J, De Biasi M. Nicotinic receptors in the habenulo-interpeduncular system are necessary for nicotine withdrawal in mice. J Neurosci. 2009;29:3014-8 pubmed publisher..Our data suggest that the efforts to develop new smoking cessation therapies should concentrate on these areas and receptor types. ..
- Phillips J, Ehrlichman R, Siegel S. Mecamylamine blocks nicotine-induced enhancement of the P20 auditory event-related potential and evoked gamma. Neuroscience. 2007;144:1314-23 pubmed..The results also support the hypothesis that nicotine may be beneficial to individuals with deficits in neurocognitive functions, such as those suffering from schizophrenia. ..
- Vincler M, Wittenauer S, Parker R, Ellison M, Olivera B, McIntosh J. Molecular mechanism for analgesia involving specific antagonism of alpha9alpha10 nicotinic acetylcholine receptors. Proc Natl Acad Sci U S A. 2006;103:17880-4 pubmed..Our findings not only suggest a molecular mechanism for the treatment of neuropathic pain but also demonstrate the involvement of alpha9alpha10 nAChRs in the pathophysiology of peripheral nerve injury. ..
- Chi S, Kim D, Olivera B, McIntosh J, Han K. NMR structure determination of alpha-conotoxin BuIA, a novel neuronal nicotinic acetylcholine receptor antagonist with an unusual 4/4 disulfide scaffold. Biochem Biophys Res Commun. 2006;349:1228-34 pubmed
- Exley R, Clements M, Hartung H, McIntosh J, Cragg S. Alpha6-containing nicotinic acetylcholine receptors dominate the nicotine control of dopamine neurotransmission in nucleus accumbens. Neuropsychopharmacology. 2008;33:2158-66 pubmed
- Grønlien J, Håkerud M, Ween H, Thorin Hagene K, Briggs C, Gopalakrishnan M, et al. Distinct profiles of alpha7 nAChR positive allosteric modulation revealed by structurally diverse chemotypes. Mol Pharmacol. 2007;72:715-24 pubmed..In summary, our studies reveal two distinct alpha7 PAM profiles, which could offer unique opportunities for modulating alpha7 nAChRs in vivo and in the development of novel therapeutics for central nervous system indications. ..