Neonicotinic analogues: Selective antagonists for α4β2 nicotinic acetylcholine receptors

Faundez-Parraguez, Manuel; Farias-Rabelo, Nicolas; González-Gutiérrez, Juan Pablo; Etcheverry-Berríos, Álvaro; Alzate‐Morales, Jans; Adasme‐Carreño, Francisco; Varas, Rodrigo; Bermúdez, Isabel; Iturriaga-Vásquez, Patricio

doi:10.1016/j.bmc.2013.03.024

Cited by 17 publications

(29 citation statements)

References 39 publications

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“…Thus, nicotine treatment produced a decrease in the α4 subunit and an increase in the α7 subunit expression, whereas UFR2709 elicited only a marked decrease in the expression of α4 subunit without modifying the level of the α7 counterpart. This last result is in agreement with previous data showing that UFR2709 displays higher affinity for α4β2 nAChRs than for α7 nAChRs [47]. In our opinion, it is too early to speculate about how these changes in nAChR subunit expression might relate to the effects of both drugs in zebrafish behaviour, but further experiments in this regard are warranted.…”

Section: Discussionsupporting

confidence: 92%

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Nicotinic Antagonist UFR2709 Inhibits Nicotine Reward and Decreases Anxiety in Zebrafish

et al. 2020

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Zebrafish is becoming a popular animal model in neuropharmacology and drug discovery, mainly due to its ease of handling and low costs involved in maintenance and experimental work. This animal displays a series of complex behaviours that makes it useful for assessing the effects of psychoactive drugs. Here, adult zebrafish were used for assessment of the anxiolytic and anti-addictive properties of UFR2709, a nicotinic receptor (nAChR) antagonist, using two behavioural paradigms to test for addiction, the novel tank diving test to assess anxiety and the conditioned place preference (CPP). Furthermore, the expression of nAChR subunits α4 and α7 was measured in the zebrafish brain. The results show that UFR2709 exhibits an anxiolytic effect on zebrafish and blocks the effect evoked by nicotine on CPP. Moreover, UFR2709 significantly decreased the expression of α4 nicotinic receptor subunit. This indicates that UFR2709 might be a useful drug for the treatment of nicotine addiction.

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Section: Discussionsupporting

confidence: 92%

“…Nicotine tartrate salt was used for the experiments (Sigma-Aldrich). The UFR2709 was synthetised as described previously in the literature [47]. All drugs were dissolved in systems water.…”

Section: Drugsmentioning

confidence: 99%

Nicotinic Antagonist UFR2709 Inhibits Nicotine Reward and Decreases Anxiety in Zebrafish

et al. 2020

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“…[5][6][7][8][9] In comparison, antagonists are far less studied, despite their substantial therapeutic potential. [10][11][12][13][14][15][16][17][18][19][20] Most of the available nAChR antagonists are natural products such as methyllycaconitine (MLA), αbungarotoxin, ibogaine, d-tubocurarine, α-conotoxins and dihydro-β-erythroidine (DHβE), the latter being a widely used selective antagonist of β2-containing heteromeric nAChRs and a semisynthetic member of the Erythrina alkaloid family. 21,22 We recently reported the design, synthesis and pharmacological evaluation of 21 analogs of aromatic Erythrina alkaloids as nAChR antagonists and found that the structurally simple tetrahydroisoquinoline 1 (also known as O-methylcorypalline) 23,24 displayed submicromolar binding affinity at the α4β2 nAChR and more than 300-fold binding selectivity over the α4β4, α3β4 and α7 subtypes (see Figure 1A).…”

Section: Introductionmentioning

confidence: 99%

Dual Nicotinic Acetylcholine Receptor α4β2 Antagonists/α7 Agonists: Synthesis, Docking Studies, and Pharmacological Evaluation of Tetrahydroisoquinolines and Tetrahydroisoquinolinium Salts

et al. 2018

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We describe the synthesis of tetrahydroisoquinolines and tetrahydroisoquinolinium salts together with their pharmacological properties at various nicotinic acetylcholine receptors. In general, the compounds were α4β2 nAChR antagonists, with the tetrahydroisoquinolinium salts being more potent than the parent tetrahydroisoquinoline derivatives. The most potent α4β2 antagonist, 6c, exhibited submicromolar binding K and functional IC values and high selectivity for this receptor over the α4β4 and α3β4 nAChRs. Whereas the (S)-6c enantiomer was essentially inactive at α4β2, (R)-6c was a slightly more potent α4β2 antagonist than the reference β2-nAChR antagonist DHβΕ. The observation that the α4β2 activity resided exclusively in the (R)-enantiomer was in full agreement with docking studies. Several of tetrahydroisoquinolinium salts also displayed agonist activity at the α7 nAChR. Preliminary in vivo evaluation revealed antidepressant-like effects of both (R)-5c and (R)-6c in the mouse forced swim test, supporting the therapeutic potential of α4β2 nAChR antagonists for this indication.

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“…Subunit assembly (ECD and TMD separately), was performed with the ICM software [ 19 ] using the AChBP or Torpedo nAChR as templates. All other modeling conditions were as previously described [ 20 , 21 ] (see below).…”

Section: Methodsmentioning

confidence: 99%

Similarities between the Binding Sites of SB-206553 at Serotonin Type 2 and Alpha7 Acetylcholine Nicotinic Receptors: Rationale for Its Polypharmacological Profile

et al. 2015

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Evidence from systems biology indicates that promiscuous drugs, i.e. those that act simultaneously at various protein targets, are clinically better in terms of efficacy, than those that act in a more selective fashion. This has generated a new trend in drug development called polypharmacology. However, the rational design of promiscuous compounds is a difficult task, particularly when the drugs are aimed to act at receptors with diverse structure, function and endogenous ligand. In the present work, using docking and molecular dynamics methodologies, we established the most probable binding sites of SB-206553, a drug originally described as a competitive antagonist of serotonin type 2B/2C metabotropic receptors (5-HT2B/2CRs) and more recently as a positive allosteric modulator of the ionotropic α7 nicotinic acetylcholine receptor (nAChR). To this end, we employed the crystal structures of the 5-HT2BR and acetylcholine binding protein as templates to build homology models of the 5-HT2CR and α7 nAChR, respectively. Then, using a statistical algorithm, the similarity between these binding sites was determined. Our analysis showed that the most plausible binding sites for SB-206553 at 5-HT2Rs and α7 nAChR are remarkably similar, both in size and chemical nature of the amino acid residues lining these pockets, thus providing a rationale to explain its affinity towards both receptor types. Finally, using a computational tool for multiple binding site alignment, we determined a consensus binding site, which should be useful for the rational design of novel compounds acting simultaneously at these two types of highly different protein targets.

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Neonicotinic analogues: Selective antagonists for α4β2 nicotinic acetylcholine receptors

Cited by 17 publications

References 39 publications

Nicotinic Antagonist UFR2709 Inhibits Nicotine Reward and Decreases Anxiety in Zebrafish

Nicotinic Antagonist UFR2709 Inhibits Nicotine Reward and Decreases Anxiety in Zebrafish

Dual Nicotinic Acetylcholine Receptor α4β2 Antagonists/α7 Agonists: Synthesis, Docking Studies, and Pharmacological Evaluation of Tetrahydroisoquinolines and Tetrahydroisoquinolinium Salts

Similarities between the Binding Sites of SB-206553 at Serotonin Type 2 and Alpha7 Acetylcholine Nicotinic Receptors: Rationale for Its Polypharmacological Profile

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