α4β2 nACh Receptor pharmacophore models

Glennon, Richard A.; Dukat, Małgorzata

doi:10.1016/j.bmcl.2003.07.035

Cited by 38 publications

(37 citation statements)

References 17 publications

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“…Binding Mode of Compound 1-Compound 1 defines the binding mode of the unsubstituted 1-(pyridin-3-yl)-1,4-diazepane scaffold, which is in general agreement with the classical nicotinic pharmacophore (60). As shown in Fig.…”

Section: Evaluation Of Ls-achbp As Model System For Nachr ␣4␤2supporting

confidence: 72%

Intersubunit Bridge Formation Governs Agonist Efficacy at Nicotinic Acetylcholine α4β2 Receptors

Rohde

Ahring

Jensen

et al. 2012

Journal of Biological Chemistry

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Background: Molecular features governing ␣4␤2 nAChRs efficacy have remained elusive. Results: Binding studies, electrophysiology, and structural data from co-crystallization with Ls-AChBP are reported for a series of ␣4␤2 agonists. Conclusion: Direct halogen bonds and an invariant Loop-C suggest that intersubunit bridge formation governs efficacy. Significance: The data provide a structural basis for understanding of efficacy levels at nAChRs.

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Section: Evaluation Of Ls-achbp As Model System For Nachr ␣4␤2supporting

confidence: 72%

Intersubunit Bridge Formation Governs Agonist Efficacy at Nicotinic Acetylcholine α4β2 Receptors

Rohde

Ahring

Jensen

et al. 2012

Journal of Biological Chemistry

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“…However, ligands are known for which the pharmacophoric distance is higher even than that found for nicotine and water: for instance (Chart 3), in 4-(3'-hydroxyphenyl)-1,1-dimethylpiperazinium iodide (the phenol analogue of DMPP), the distance between the H-bond forming group and the cationic nitrogen is 7.5 Å, while for 4-(3-pyridyl)but-3-yn-1-amines the low energy conformers have distances higher than 8 Å. 59 Both compounds are reported to bind with nanomolar affinity to the receptor. 50,60 So it can be suggested that ligands dock into the active site in a way that allows them to interact with different residues according to their own distance between the pharmacophoric points.…”

mentioning

confidence: 85%

“…Compounds 1 and 6 (as well as their methiodides 4 and 7) show a distance between the Hbond acceptor aromatic nitrogen and the cationic nitrogen of 6.5-6.6 Å, therefore higher than that proposed by pharmacophoric models, [47][48][49] but in the same range as that obtained considering the additional water molecule which connects the nicotine pyridyl nitrogen and the protein in the crystal structure of the complex between AChBP and nicotine. The possible presence of a water molecule is the basis of the "water-extension concept", 59 which suggests that a short ligand such as nicotine (N-N distance 4.8 Å) can be transformed into a longer ligand whose distance between the cationic nitrogen and the H-bond forming group (pyridyl nitrogen or water oxigen) is higher (6.7 Å in the crystal structure); this would explain the wide range of the proposed pharmacophoric distances. In addition, the water molecule could allow the interaction of the protein with a ligand having an H-bond acceptor as well as donor group in the suitable position.…”

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confidence: 99%

Design, synthesis and binding affinity of new nicotinic ligands

Guandalini¹,

Martini²,

Gratteri³

et al. 2006

Arkivoc

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Nicotinic ligands can be potentially useful as drugs for the management of several important pathologies as well as pharmacological tools to characterize nicotinic receptor subtypes. The design of new nicotinic ligands has been carried out by applying the 3D database search method; thus, the Cambridge Structural Database has been scanned with a query consisting in a pharmacophore substructure with 3D constraints. The nicotinic pharmacophoric features have been obtained from the structure of pyrido[3,4-b]homotropane (PHT), which represents a rigid template. The results of the query suggested the aminoalkylquinoline moiety as simple scaffold, and it was further refined using molecular modeling. Some of the synthesized compounds were found to interact with the central nicotinic receptor on rat cerebral cortex, showing affinity in the nanomolar range and displaying analgesic properties. The possible binding mode of these substances with a homology-built model of the nicotinic receptor has been analyzed by means of induced fit studies.

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“…4.8 . With the coming out of epibatidine as a high-affinity nicotinic agonist, Glennon et al proposed a new model indicating an optimal d of 5.1 -5.5 [31], which was further extended by Abreo et al to 6.1 [32], but it has not been agreed upon a precise nicotine pharmacophore by the medicinal chemists [33].…”

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confidence: 99%

The Influence of the Nitrogen Substitution in Three Cytisine Derivatives as Ligands for the Neuronal nAChRs: A Structural and Theoretical Study

Bombieri

Meneghetti

Artali

et al. 2008

Chemistry & Biodiversity

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Three cytisine derivatives, (-)-(7R,9S)-1-phenyl-3-(cytisin-12-yl)propan-1-one (1), (-)-(7R,9S)-1-phenyl-2-(cytisin-12-yl)ethane (2), and (-)-(7R,9S)-1,2-bis(cytisin-12-yl)ethane (3), with different electronic and steric features have been characterized by X-ray analysis and theoretical calculations in order to evaluate how structural modulations affect the intrinsic binding affinity at the neuronal nicotinic receptors (nAChRs). The crystal structures of 1 and 2, which display comparable affinities, are characterized by the same conformation of the cytisine moiety with different orientations of the substituent at N2. In 3, two independent molecules have the pyridinone rings diversely oriented. This compound has a lower affinity with respect to 1 and 2, but it increases the expression of neuronal nAChRs. Compounds 1, 2, and 3 retain the key prerequisite of the classical pharmacophoric models, with sp(3)-N-atom--HBA distances close to the expected value, both in solid state and in solution (theoretical calculations), where, in contrast with the extended in the crystal state, a curled-up conformation has been found, though maintaining the N-substituent in equatorial position.

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α4β2 nACh Receptor pharmacophore models

Cited by 38 publications

References 17 publications

Intersubunit Bridge Formation Governs Agonist Efficacy at Nicotinic Acetylcholine α4β2 Receptors

Intersubunit Bridge Formation Governs Agonist Efficacy at Nicotinic Acetylcholine α4β2 Receptors

Design, synthesis and binding affinity of new nicotinic ligands

The Influence of the Nitrogen Substitution in Three Cytisine Derivatives as Ligands for the Neuronal nAChRs: A Structural and Theoretical Study

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