From pyrrolidinyl-benzodioxane to pyrrolidinyl-pyridodioxanes, or from unselective antagonism to selective partial agonism at α4β2 nicotinic acetylcholine receptor

Determinants for α4β2 vs. α3β4 Subtype Selectivity of Pyrrolidine-Based nAChRs Ligands: A Computational Perspective with Focus on Recent cryo-EM Receptor Structures

“…Whereas (S,R)-14 is stabilized at the α4β2 nAChR by π-π stacking with β2-Phe119, at the α3β4 the pyridyl ring bends out with a wide angle of 51 • and an overall RMSD of 2.7792 Å, loosing the interaction with the structural water molecule. The same effect was evident for (S,R)-33 (discussed later), its fully rigidified analogue previously reported [5,33]. Furthermore, the binding conformation of (S,R)-14 at the α4β2 nAChR superimposes well with that of (S,R)-33, positioning the α-methyl functional group in the area where the corresponding C3 of the benzodioxane is placed (compare Figure 7D with Figure 10B).…”

“…The two stereoisomers with absolute configuration "R" at the pyrrolidine stereocenter were devoid of affinity, while (S,S)-21 and (S,R)-21 had submicromolar α4β2 K i s of 0.47 µM and 0.26 µM, respectively. Later, they were shown to be micromolar binders at the α3β4 [5]. In 2011, we developed the series of 7-substituted analogs 2, 22-28 (Table 4), among which only (S,R)-2 was able to bind at the α4β2 nAChR (K i = 0.012 µM).…”

“…In 2017, we developed 33-36, the four regioisomeric pyridodioxane-based analogs of (S,R)-21, in both the (S,R) and the (S,S) diasteromeric forms (Table 5) [5]. (S,R)-33 was the only compound retaining the submicromolar binding affinity at the α4β2 subtype (Ki = 0.41 µM), with a 40-fold α4β2 vs. α3β4 selectivity ratio.…”

“…The α4β2 nAChR, the major subtype in the brain, is primarily involved in such a strategy as its ligands, full or partial agonists, have shown a therapeutic potential as, for instance, antidepressants and drug cessation aids [2][3][4]. However, structural features relevant for full or partial agonism and for selectivity over the ganglionic α3β4 nicotinic subtype, which both condition the therapeutic range, remain two topical issues in SAR analysis and design of α4β2 ligands [5][6][7], undoubtedly more challenging than α4β2-α7 selectivity, which is generally more inherent in both highly affinitive α4β2 and α7 ligands [6,8]. On this matter, the structures of both human α4β2 and α3β4 receptors, recently determined by cryo-electron microscopy, can be a potent investigation tool suggesting new principles of agonist efficacy and, even more, of subtype selectivity [9,10].…”

“…In the last 15 years, we have designed and developed some series of chiral α4β2 ligands, full and partial agonists and antagonists [22], initially linking the N-methyl-2pyrrolidinyl residue, typical of nicotinoids, to C(2) of 1,4-benzodioxane [23,24], a scaffold widely employed to design bioactive molecules [25][26][27][28][29] and, in this instance, to mimick the aryloxymethyl portion of prolinol aryl ethers, well known high-affinity α4β2 ligands such as A-84543 [30] (Figure 1B; for benzodioxane scaffold numbering see (S,R)-21 formula). Successive steps were the decoration of the benzodioxane by introducing substituents at its C (7) [31], deconstruction of the dioxane ring to give new phenyl and pyridyl ethers of prolinol [7,32], replacement of benzene with pyridine to give the four regioisomeric pyridodioxanes [5], and again benzodioxane decoration with substituents at C(6) and C(5) [33]. In each of these series of prolinol aryl ethers or benzodioxane/pyridodioxane derivatives some compounds, as exemplified in Figure 1, exhibited one to hundred nanomolar α4β2 affinity and some of these also from good to high functional and binding selectivity over the α3β4 subtype.…”