Journal Article

Unlocking nicotinic selectivity via direct C‒H functionalization of (−)-cytisine


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.

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Rego Campello, Hugo
Del Villar, Silvia G.
Honraedt, Aurélien
Minguez, Teresa
Oliveira, A. Sofia F.
Ranaghan, Kara E.
Shoemark, Deborah K.
Bermudez, Isabel
Gotti, Cecilia
Sessions, Richard B.
Mulholland, Adrian J.
Wonnacott, Susan
Gallagher, Timothy

Oxford Brookes departments

Faculty of Health and Life Sciences\Department of Biological and Medical Sciences


Year of publication: 2018
Date of RADAR deposit: 2018-08-06

Creative Commons License This work is licensed under a Creative Commons Attribution 4.0 International License

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