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Unlocking Nicotinic Selectivity via Direct C‒H Functionalization of ()-Cytisine

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Unlocking Nicotinic Selectivity via Direct C‒H Functionalization of ()-Cytisine. / Rego Campello, Hugo; Garcia Del Villar, Silvia; Honraedt, Aurelien; Minguez Viñas, Teresa; Oliveira, Sofia; Ranaghan, Kara; Shoemark, Deborah; Bermudez, Isabel; Gotti, Cecilia ; Sessions, Richard; Mulholland, Adrian; Wonnacott, Susan; Gallagher, Tim.

In: Chem, Vol. 4, No. 7, 12.07.2018, p. 1710-1725.

Research output: Contribution to journalArticle

Harvard

Rego Campello, H, Garcia Del Villar, S, Honraedt, A, Minguez Viñas, T, Oliveira, S, Ranaghan, K, Shoemark, D, Bermudez, I, Gotti, C, Sessions, R, Mulholland, A, Wonnacott, S & Gallagher, T 2018, 'Unlocking Nicotinic Selectivity via Direct C‒H Functionalization of ()-Cytisine', Chem, vol. 4, no. 7, pp. 1710-1725. https://doi.org/10.1016/j.chempr.2018.05.007

APA

Rego Campello, H., Garcia Del Villar, S., Honraedt, A., Minguez Viñas, T., Oliveira, S., Ranaghan, K., ... Gallagher, T. (2018). Unlocking Nicotinic Selectivity via Direct C‒H Functionalization of ()-Cytisine. Chem, 4(7), 1710-1725. https://doi.org/10.1016/j.chempr.2018.05.007

Vancouver

Rego Campello H, Garcia Del Villar S, Honraedt A, Minguez Viñas T, Oliveira S, Ranaghan K et al. Unlocking Nicotinic Selectivity via Direct C‒H Functionalization of ()-Cytisine. Chem. 2018 Jul 12;4(7):1710-1725. https://doi.org/10.1016/j.chempr.2018.05.007

Author

Rego Campello, Hugo ; Garcia Del Villar, Silvia ; Honraedt, Aurelien ; Minguez Viñas, Teresa ; Oliveira, Sofia ; Ranaghan, Kara ; Shoemark, Deborah ; Bermudez, Isabel ; Gotti, Cecilia ; Sessions, Richard ; Mulholland, Adrian ; Wonnacott, Susan ; Gallagher, Tim. / Unlocking Nicotinic Selectivity via Direct C‒H Functionalization of ()-Cytisine. In: Chem. 2018 ; Vol. 4, No. 7. pp. 1710-1725.

Bibtex

@article{330e99ead84d48ac9da62c1a4347bd53,
title = "Unlocking Nicotinic Selectivity via Direct C‒H Functionalization of ()-Cytisine",
abstract = "Differentiating nicotinic acetylcholine receptors (nAChR) to target the high-affinity nicotine α4β2 subtype is a major challenge in developing effective addiction therapies. Although cytisine 1 and varenicline 2 (current smoking-cessation agents) are partial agonists of α4β2, these drugs display full agonism at the α7 nAChR subtype. Site-specific modification of (−)-cytisine via Ir-catalyzed C‒H activation provides access to C(10) variants 6–10, 13, 14, 17, 20, and 22, and docking studies reveal that C(10) substitution targets the complementary region of the receptor binding site, mediating subtype differentiation. C(10)-modified cytisine ligands retain affinity for α4β2 nAChR and are partial agonists, show enhanced selectivity for α4β2 versus both α3β4 and α7 subtypes, and critically, display negligible activity at α7. Molecular dynamics simulations link the C(10) moiety to receptor subtype differentiation; key residues beyond the immediate binding site are identified, and molecular-level conformational behavior responsible for these crucial differences is characterized. Molecular locksmithing is the use of precision chemical keys for biological locks. Nicotinic acetylcholine receptors (nAChR) associated with acetylcholine neurotransmission are linked to public health issues, notably tobacco addiction. Why is this important? Smoking kills seven million people annually and imposes a huge burden in terms of healthcare and lost productivity. The ability to design a molecule to achieve high receptor selectivity is paramount for the success of smoking cessation: poor selectivity is typically accompanied by (adverse) side effects. We have modified cytisine, a known “nicotinic activator,” in a very direct and versatile manner to suppress a particular characteristic: activation of the α7 subtype of nAChR. Computational molecular simulation of the protein-ligand complexes links these structural changes to a ligand's activity, facilitating the design of precision “molecular keys” for better discrimination of receptor subtypes and offering the potential of more targeted therapies. Efficient access to C(10) of (−)-cytisine via C‒H activation provides access to enantiomerically pure nicotinic acetylcholine receptor ligands that target the high-affinity nicotine α4β2 subtype with enhanced selectivity. These C(10) cytisine variants retain a partial agonist profile at the α4β2 subtype but, critically, display negligible activity at the α7 receptor subtype. Using computational methods, Gallagher and colleagues link receptor selectivity to key protein residues associated with, as well as beyond, the immediate ligand binding site.",
keywords = "cytisine, pyridone, CH activation, iridium borylation, α4β2 nicotinic receptor, partial agonist, smoking cessation, molecular dynamics, binding modes",
author = "{Rego Campello}, Hugo and {Garcia Del Villar}, Silvia and Aurelien Honraedt and {Minguez Vi{\~n}as}, Teresa and Sofia Oliveira and Kara Ranaghan and Deborah Shoemark and Isabel Bermudez and Cecilia Gotti and Richard Sessions and Adrian Mulholland and Susan Wonnacott and Tim Gallagher",
year = "2018",
month = "7",
day = "12",
doi = "10.1016/j.chempr.2018.05.007",
language = "English",
volume = "4",
pages = "1710--1725",
journal = "Chem",
issn = "2451-9308",
publisher = "Cell Press",
number = "7",

}

RIS - suitable for import to EndNote

TY - JOUR

T1 - Unlocking Nicotinic Selectivity via Direct C‒H Functionalization of ()-Cytisine

AU - Rego Campello, Hugo

AU - Garcia Del Villar, Silvia

AU - Honraedt, Aurelien

AU - Minguez Viñas, Teresa

AU - Oliveira, Sofia

AU - Ranaghan, Kara

AU - Shoemark, Deborah

AU - Bermudez, Isabel

AU - Gotti, Cecilia

AU - Sessions, Richard

AU - Mulholland, Adrian

AU - Wonnacott, Susan

AU - Gallagher, Tim

PY - 2018/7/12

Y1 - 2018/7/12

N2 - Differentiating nicotinic acetylcholine receptors (nAChR) to target the high-affinity nicotine α4β2 subtype is a major challenge in developing effective addiction therapies. Although cytisine 1 and varenicline 2 (current smoking-cessation agents) are partial agonists of α4β2, these drugs display full agonism at the α7 nAChR subtype. Site-specific modification of (−)-cytisine via Ir-catalyzed C‒H activation provides access to C(10) variants 6–10, 13, 14, 17, 20, and 22, and docking studies reveal that C(10) substitution targets the complementary region of the receptor binding site, mediating subtype differentiation. C(10)-modified cytisine ligands retain affinity for α4β2 nAChR and are partial agonists, show enhanced selectivity for α4β2 versus both α3β4 and α7 subtypes, and critically, display negligible activity at α7. Molecular dynamics simulations link the C(10) moiety to receptor subtype differentiation; key residues beyond the immediate binding site are identified, and molecular-level conformational behavior responsible for these crucial differences is characterized. Molecular locksmithing is the use of precision chemical keys for biological locks. Nicotinic acetylcholine receptors (nAChR) associated with acetylcholine neurotransmission are linked to public health issues, notably tobacco addiction. Why is this important? Smoking kills seven million people annually and imposes a huge burden in terms of healthcare and lost productivity. The ability to design a molecule to achieve high receptor selectivity is paramount for the success of smoking cessation: poor selectivity is typically accompanied by (adverse) side effects. We have modified cytisine, a known “nicotinic activator,” in a very direct and versatile manner to suppress a particular characteristic: activation of the α7 subtype of nAChR. Computational molecular simulation of the protein-ligand complexes links these structural changes to a ligand's activity, facilitating the design of precision “molecular keys” for better discrimination of receptor subtypes and offering the potential of more targeted therapies. Efficient access to C(10) of (−)-cytisine via C‒H activation provides access to enantiomerically pure nicotinic acetylcholine receptor ligands that target the high-affinity nicotine α4β2 subtype with enhanced selectivity. These C(10) cytisine variants retain a partial agonist profile at the α4β2 subtype but, critically, display negligible activity at the α7 receptor subtype. Using computational methods, Gallagher and colleagues link receptor selectivity to key protein residues associated with, as well as beyond, the immediate ligand binding site.

AB - Differentiating nicotinic acetylcholine receptors (nAChR) to target the high-affinity nicotine α4β2 subtype is a major challenge in developing effective addiction therapies. Although cytisine 1 and varenicline 2 (current smoking-cessation agents) are partial agonists of α4β2, these drugs display full agonism at the α7 nAChR subtype. Site-specific modification of (−)-cytisine via Ir-catalyzed C‒H activation provides access to C(10) variants 6–10, 13, 14, 17, 20, and 22, and docking studies reveal that C(10) substitution targets the complementary region of the receptor binding site, mediating subtype differentiation. C(10)-modified cytisine ligands retain affinity for α4β2 nAChR and are partial agonists, show enhanced selectivity for α4β2 versus both α3β4 and α7 subtypes, and critically, display negligible activity at α7. Molecular dynamics simulations link the C(10) moiety to receptor subtype differentiation; key residues beyond the immediate binding site are identified, and molecular-level conformational behavior responsible for these crucial differences is characterized. Molecular locksmithing is the use of precision chemical keys for biological locks. Nicotinic acetylcholine receptors (nAChR) associated with acetylcholine neurotransmission are linked to public health issues, notably tobacco addiction. Why is this important? Smoking kills seven million people annually and imposes a huge burden in terms of healthcare and lost productivity. The ability to design a molecule to achieve high receptor selectivity is paramount for the success of smoking cessation: poor selectivity is typically accompanied by (adverse) side effects. We have modified cytisine, a known “nicotinic activator,” in a very direct and versatile manner to suppress a particular characteristic: activation of the α7 subtype of nAChR. Computational molecular simulation of the protein-ligand complexes links these structural changes to a ligand's activity, facilitating the design of precision “molecular keys” for better discrimination of receptor subtypes and offering the potential of more targeted therapies. Efficient access to C(10) of (−)-cytisine via C‒H activation provides access to enantiomerically pure nicotinic acetylcholine receptor ligands that target the high-affinity nicotine α4β2 subtype with enhanced selectivity. These C(10) cytisine variants retain a partial agonist profile at the α4β2 subtype but, critically, display negligible activity at the α7 receptor subtype. Using computational methods, Gallagher and colleagues link receptor selectivity to key protein residues associated with, as well as beyond, the immediate ligand binding site.

KW - cytisine

KW - pyridone

KW - CH activation

KW - iridium borylation

KW - α4β2 nicotinic receptor

KW - partial agonist

KW - smoking cessation

KW - molecular dynamics

KW - binding modes

UR - http://www.scopus.com/inward/record.url?scp=85047789313&partnerID=8YFLogxK

U2 - 10.1016/j.chempr.2018.05.007

DO - 10.1016/j.chempr.2018.05.007

M3 - Article

VL - 4

SP - 1710

EP - 1725

JO - Chem

JF - Chem

SN - 2451-9308

IS - 7

ER -