Central Nicotinic Receptors: Structure, Function, Ligands, and Therapeutic Potential

Romanelli, Maria Novella; Gratteri, Paola; Guandalini, Luca; Martini, Elisabetta; Bonaccini, Claudia; Gualtieri, Fulvio

doi:10.1002/cmdc.200600207

Cited by 157 publications

(131 citation statements)

References 266 publications

(261 reference statements)

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“…The nAChR family members are also the prototypes of a large class of channels termed Cys-loop (or pentameric) receptors, which are essential for learning, memory, and sensory perception and are implicated in numerous neurological disorders, including Alzheimer disease, Parkinson disease, and schizophrenia (4,5). Of the 17 genes that code for subunits of the nAChR, 10 produce ␣ subunits.…”

Section: Nicotinic Acetylcholine Receptors (Nachrs)mentioning

confidence: 99%

Evidence for an Extended Hydrogen Bond Network in the Binding Site of the Nicotinic Receptor

Blum

Gleitsman

Lester

et al. 2011

Journal of Biological Chemistry

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The defining feature of the ␣ subunits of the family of nicotinic acetylcholine receptors is a vicinal disulfide between Cys-192 and Cys-193. Although this structure has played a pivotal role in a number of pioneering studies of nicotinic receptors, its functional role in native receptors remains uncertain. Using mutant cycle analysis and unnatural residue mutagenesis, including backbone mutagenesis of the peptide bond of the vicinal disulfide, we have established the presence of a network of hydrogen bonds that extends from that peptide NH, across a ␤ turn to another backbone hydrogen bond, and then across the subunit interface to the side chain of a functionally important Asp residue in the non-␣ subunit. We propose that the role of the vicinal disulfide is to distort the ␤ turn and thereby properly position a backbone NH for intersubunit hydrogen bonding to the key Asp.

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Section: Nicotinic Acetylcholine Receptors (Nachrs)mentioning

confidence: 99%

Evidence for an Extended Hydrogen Bond Network in the Binding Site of the Nicotinic Receptor

Blum

Gleitsman

Lester

et al. 2011

Journal of Biological Chemistry

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“…1), a nicotine-related a4b2 selective full agonist, which entered Phase I for the treatment of cognitive dysfunction and was later on discontinued. 2,7,17 A further relevant example of structural analogue of epibatidine is the unsaturated derivative (±)-UB-165 5, containing the 9-azabicyclo[4.2.1]nonene skeleton, a high affinity nicotinic partial agonist which allowed to clarify the involvement of the a4b2 subtype in modulating dopamine release from rat striatal synaptosomes. 18,19 0960-894X/$ -see front matter Ó…”

mentioning

confidence: 99%

“…Neuronal nicotinic acetylcholine receptors (nAChRs) make up a family of pentameric ligand-gated ion channels, which are formed by combinations of alpha and beta subunits 1,2 or exist as homopentamers, in the cases of a7, a8, and a9 receptors, which are inhibited by a-bungarotoxin. 3 To date, nine a (a2-a10) and three b (b2-b4) isoforms have been characterized, though only a relatively small subset of combinations generates functionally and physiologically relevant channels.…”

mentioning

confidence: 99%

“…2,8 As far as the number of nicotinic agonists isolated from natural sources is taken into consideration, 9 (À)-epibatidine 2 ( Fig. 1), a highly toxic alkaloid identified in the skin of the Ecuadorian frog Epipedobates tricolor, 10 has inspired a huge amount of research aimed at designing subtype selective nicotinic agonists.…”

mentioning

confidence: 99%

“…1), a highly toxic alkaloid identified in the skin of the Ecuadorian frog Epipedobates tricolor, 10 has inspired a huge amount of research aimed at designing subtype selective nicotinic agonists. 1,2,9,11,12 Although the pharmacological effects of (À)-2 are mediated by a variety of nAChRs, 13 which preclude any therapeutic potential for epibatidine, the analgesic potency, roughly 100 times higher than that of morphine and 30 times higher than that of nicotine, has been attributed to its high affinity for the a4b2 subtype. Worth mentioning, (À)-2 and (+)-2 are characterized by similar affinities for nAChRs and almost identical ED 50 values in the mouse tail-flick antinociception assay.…”

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confidence: 99%

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Epiboxidine and novel-related analogues: A convenient synthetic approach and estimation of their affinity at neuronal nicotinic acetylcholine receptor subtypes

Rizzi

Dallanoce

Matera

et al. 2008

Bioorganic & Medicinal Chemistry Letters

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a b s t r a c tRacemic exo-epiboxidine 3, endo-epiboxidine 6, and the two unsaturated epiboxidine-related derivatives 7 and 8 were efficiently prepared taking advantage of a palladium-catalyzed Stille coupling as the key step in the reaction sequence. The target compounds were assayed for their binding affinity at neuronal a4b2 and a7 nicotinic acetylcholine receptors. Epiboxidine 3 behaved as a high affinity a4b2 ligand (K i = 0.4 nM) and, interestingly, evidenced a relevant affinity also for the a7 subtype (K i = 6 nM). Derivative 7, the closest analogue of 3 in this group, bound with lower affinity at both receptor subtypes (K i = 50 nM for a4b2 and K i = 1.6 lM for a7) evidenced a gain in the a4b2 versus a7 selectivity when compared with the model compound.Ó 2008 Elsevier Ltd. All rights reserved.Neuronal nicotinic acetylcholine receptors (nAChRs) make up a family of pentameric ligand-gated ion channels, which are formed by combinations of alpha and beta subunits 1,2 or exist as homopentamers, in the cases of a7, a8, and a9 receptors, which are inhibited by a-bungarotoxin. 3 To date, nine a (a2-a10) and three b (b2-b4) isoforms have been characterized, though only a relatively small subset of combinations generates functionally and physiologically relevant channels. 4 Nicotinic receptors are widely distributed in the brain, where they primarily modulate the release of other neurotransmitters and, to a lesser extent, mediate synaptic transmission. 5 Neuronal nAChRs, selectively activated by (S)-nicotine 1 (Fig. 1), are involved in various processes such as cognition, learning and memory, cerebral blood flow and metabolism, as well as an array of pathological conditions such as Alzheimer's and Parkinson's diseases, mild cognitive impairment (MCI), schizophrenia, epilepsy, Tourette's syndrome, anxiety, depression, attention-deficit hyperactivity disorder (ADHD), and nicotine addiction.1,2,6,7The heteromeric a4b2 receptors, the most abundant subtype in the mammalian CNS, and the homomeric a7 channels are privileged biological targets in the search for selective nAChR ligands with therapeutic potential. 2,8 As far as the number of nicotinic agonists isolated from natural sources is taken into consideration, 9 (À)-epibatidine 2 (Fig. 1), a highly toxic alkaloid identified in the skin of the Ecuadorian frog Epipedobates tricolor, 10 has inspired a huge amount of research aimed at designing subtype selective nicotinic agonists. 1,2,9,11,12 Although the pharmacological effects of (À)-2 are mediated by a variety of nAChRs, 13 which preclude any therapeutic potential for epibatidine, the analgesic potency, roughly 100 times higher than that of morphine and 30 times higher than that of nicotine, has been attributed to its high affinity for the a4b2 subtype. Worth mentioning, (À)-2 and (+)-2 are characterized by similar affinities for nAChRs and almost identical ED 50 values in the mouse tail-flick antinociception assay. 13d,14,15 Among the synthetic epibatidine-related compounds, (±)-epiboxidine 3 (Fig. 1), in which ...

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Lithiated Aza‐Heterocycles in Modern Synthesis

Fort

Comoy

2014

Lithium Compounds in Organic Synthesis

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Introduction Functional nitrogen-containing heteroaromatic compounds, especially sixmembered ones (pyridines, diazines, quinolines, and their fused derivatives), have attracted the attention of chemists worldwide because they play an important role in the development of new pharmaceuticals [1], agrochemicals [2], catalysts [3], or materials [4] (including polymers).Besides the classical reactions (i.e., electrophilic heteroaromatic substitutions on heterocycles or single electron-transfer (SET) mediated reactions with brominated derivatives) [5] and ex nihilo ring syntheses [6], metallation reactions providing organolithium compounds are of particular interest because they allow the direct functionalization starting from bare or sparsely substituted heterocycles intrinsically more acidic than similar benzene-ring systems. However, the strong bases used for metallation as well as the prepared organolithiums also exhibit a large propensity for nucleophilic addition. Further, though numerous methods have been described for the single derivatization, multiple functionalization often appears much more sensitive and difficult because of the complexation or aggregation phenomena observed either with primary substituents or with the nitrogen atom in the heterocycle itself. These complex phenomena, together with the variation in reaction conditions (temperature, solvent, ratio), produce various competitive reaction pathways. Thus, an arsenal of methodologies has then been developed to tune the regio-, chemio-, and sometimes stereoselectivities. The goal is generally to control these additional influences, providing variation of kinetic or thermodynamic acidity at various sites susceptible to lithiation.With a special focus on pyridines, quinolines, diazines, and fused pyridinic compounds, this chapter describes organolithium tools that allow (i) direct derivatization of bare N-containing heteroaromatics; (ii) metallation of dipolar adducts of pyridines and analogs; (iii) halogen/Li exchanges; (iv) ring metallation by using directing metallation groups; (v) lithiation invoking an halogen dance; and (vi) lateral and remote lithiations (Scheme 15.1). Next, the usefulness of these tools, often Lithium Compounds in Organic Synthesis: From Fundamentals to Applications, First Edition. Edited by Renzo Luisi and Vito Capriati.

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Central Nicotinic Receptors: Structure, Function, Ligands, and Therapeutic Potential

Cited by 157 publications

References 266 publications

Evidence for an Extended Hydrogen Bond Network in the Binding Site of the Nicotinic Receptor

Evidence for an Extended Hydrogen Bond Network in the Binding Site of the Nicotinic Receptor

Epiboxidine and novel-related analogues: A convenient synthetic approach and estimation of their affinity at neuronal nicotinic acetylcholine receptor subtypes

Lithiated Aza‐Heterocycles in Modern Synthesis

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