The thermodynamic profile and molecular interactions of a C(9)-cytisine derivative-binding acetylcholine-binding protein from Aplysia californica

Abstract

Cytisine, a natural product with high affinity for clinically relevant nicotinic acetylcholine receptors (nAChRs), is used as a smoking‐cessation agent. The compound displays an excellent clinical profile and hence there is an interest in derivatives that may be further improved or find use in the treatment of other conditions. Here, the binding of a cytisine derivative modified by the addition of a 3‐(hydroxypropyl) moiety (ligand 4) to Aplysia californica acetylcholine‐binding protein (AcAChBP), a surrogate for nAChR orthosteric binding sites, was investigated. Isothermal titration calorimetry revealed that the favorable binding of cytisine and its derivative to AcAChBP is driven by the enthalpic contribution, which dominates an unfavorable entropic component. Although ligand 4 had a less unfavorable entropic contribution compared with cytisine, the affinity for AcAChBP was significantly diminished owing to the magnitude of the reduction in the enthalpic component. The high‐resolution crystal structure of the AcAChBP–4 complex indicated close similarities in the protein–ligand interactions involving the parts of 4 common to cytisine. The point of difference, the 3‐(hydroxypropyl) substituent, appears to influence the conformation of the Met133 side chain and helps to form an ordered solvent structure at the edge of the orthosteric binding site.

Delineating the activity of the potent nicotinic acetylcholine receptor agonists (+)-anatoxin-a and (−)-hosieine-A

“…For (À)-hosieine-A the K d values are 0.025 AE 0.005 mM (molar ratio 0.7:1) and 0.040 AE 0.001 mM. These values indicate a much higher affinity for the protein compared with (À)-cytisine, for which ITC-derived K d values of 1.6 mM and 0.60 AE 0.03 mM are reported (Table 4; Rucktooa et al, 2012;Davis et al, 2020). For comparison, varenicline is reported to have a K d of 0.34 mM obtained by ITC (Rucktooa et al, 2012).…”

“…Structures were solved by molecular replacement using Phaser (McCoy et al, 2007). The initial polypeptide model for the AcAChBP-(+)-anatoxin-a complex structure comprised two pentamers of an AcAChBP structure (PDB entry 2byn; Davis et al, 2020). Once refined, the polypeptide of the complex provided the starting model for the isomorphous AcAChBP-(À)-hosieine-A structure.…”

Sparteine Thiourea: The Synthesis of an N Chiral Bispidine-Quinolizidine-Derived Organocatalyst and Applications in Asymmetric Synthesis of Dihydropyrano[c]chromenes

“…Bispidine-type ligands, in contrast, are readily obtained and more easily derived, without a significant loss of bridged bicyclic 1,3-diamine-based rigidity. (−)-Cytisine 3 , a fusion of bispidine with 2-pyridinone, is well recognized as a nicotinic acetylcholine receptor (nAChR) of the central nervous system and used as a smoking cessation drug . Except for its biological and pharmaceutical uses, O’Brien et al have utilized (−)-cytisine in the semisynthesis of (+)-sparteine surrogate 4 , shown in Figure , which exhibits a similar yield and a similar enantioselectivity in several asymmetric syntheses compared to those of (+)-sparteine.…”