Abstract
Summary 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.
Highlights
Validated links exist between neuronal nicotinic acetylcholine receptors[1,2,3,4] and a range of neurodegenerative[5] and psychiatric diseases.[6]
The partial agonist profile of 1 at a4b2 nicotinic acetylcholine receptors (nAChR) differentiates this natural product from full agonists, such as acetylcholine
This chemistry leads efficiently and flexibly to cytisine variants with (1) enhanced a4b2 selectivity that retain the essential partial agonist profile suited to smoking cessation, and (2) that show a negligible agonist profile for a7 nAChR
Summary
Validated links exist between neuronal nicotinic acetylcholine receptors (nAChR)[1,2,3,4] and a range of neurodegenerative[5] and psychiatric diseases.[6] Interest in these conditions, together with the broader public health issue of tobacco consumption and addiction,[7,8] a global challenge highlighted by the landmark World Health Organization Framework Convention on Tobacco Control,[9] has driven the discovery and evaluation of small molecule ligands for therapeutic intervention, notably for smoking cessation.[10,11] These molecules are often derived from natural product leads, such as nicotine, but a continuing goal is to identify ligands with higher selectivity for targeting nAChR subtypes such as a4b2 (the prime receptor for smoked nicotine because of its high-affinity nicotine binding sites) coupled with sufficient bioavailability to enable central nervous system penetration.[12,13]. A synthetic variant, varenicline 2 (launched in 2006 as Champix and Chantix; Figure 1)[20,21,22,23] offers a broadly comparable profile with that of 1 for a4b2
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