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

Abstract

The selectivity of α4β2 nAChR agonists over the α3β4 nicotinic receptor subtype, predominant in ganglia, primarily conditions their therapeutic range and it is still a complex and challenging issue for medicinal chemists and pharmacologists. Here, we investigate the determinants for such subtype selectivity in a series of more than forty α4β2 ligands we have previously reported, docking them into the structures of the two human subtypes, recently determined by cryo-electron microscopy. They are all pyrrolidine based analogues of the well-known α4β2 agonist N-methylprolinol pyridyl ether A-84543 and differ in the flexibility and pattern substitution of their aromatic portion. Indeed, the direct or water mediated interaction with hydrophilic residues of the relatively narrower β2 minus side through the elements decorating the aromatic ring and the stabilization of the latter by facing to the not conserved β2-Phe119 result as key distinctive features for the α4β2 affinity. Consistently, these compounds show, despite the structural similarity, very different α4β2 vs. α3β4 selectivities, from modest to very high, which relate to rigidity/extensibility degree of the portion containing the aromatic ring and to substitutions at the latter. Furthermore, the structural rationalization of the rat vs. human differences of α4β2 vs. α3β4 selectivity ratios is here proposed.

From 2-Triethylammonium Ethyl Ether of 4-Stilbenol (MG624) to Selective Small-Molecule Antagonists of Human α9α10 Nicotinic Receptor by Modifications at the Ammonium Ethyl Residue

“…As in our previous investigation on onium-alkyloxy-stilbene based compounds, the pharmacological characterization of this new series of stilbenol ammoniumalkyl ethers, formally derived from the lead 1 by modification of the cationic head (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17) or rigidification of the O-N linker (18)(19)(20)(21)(22)(23)(24)(25)(26)(27), started from the evaluation of the α7-nAChR binding affinity by α-Bgtx displacement. This is indicative of competition for the same ACh orthosteric binding sites of this receptor and, in the development of our investigation, a useful guiding criterion in selecting candidates for functional study at both α7and α9α10-nAChR.…”

“…As for the selectivity against the α3β4 nAChR subtype, this is, in our experience, a crucial issue for the nicotinoids we have so far developed, namely, for the stilbenol ammonium ethyl ethers as α7-α9α10 ligands , and for pyrrolidinyl-benzodioxanes as α4β2 ligands. , Otherwise, the selectivity between these two latter subtypes is less challenging. The present results indicate that dissecting the α9α10-nAChR antagonist activity from the α7-nAChR antagonism can coincide with very low α7- and α3β4-nAChR affinities.…”

Selective Potentiation of the (α4)3(β2)2 Nicotinic Acetylcholine Receptor Response by NS9283 Analogues

“…Relying on previously identified and characterized hits, and on available 3D structures of nAChR subtypes, our work has focused on developing partial agonists selective for α4β2 nAChR. − Partial agonists of α4β2 nAChR are more suitable for clinical application than full or superagonists due to their wider therapeutic range and attenuated side effects. − More recently, we have developed α4β2 agonists with receptor stoichiometry–selectivity . The α4 and β2 subunits assemble into two forms, the (α4) 2 (β2) 3 stoichiometry, which has high sensitivity to activation by agonists (HS α4β2 nAChR), and the (α4) 3 (β2) 2 stoichiometry, which has lower agonist sensitivity (LS α4β2 nAChR). − The differences in type and relative disposition of subunit interfaces between the two isoforms result in two stoichiometry-specific subunit interfaces (α4/α4 in LS α4β2; β2/β2 in HS α4β2), which can be exploited to achieve isoform selective α4β2 nAChR effects.…”

Methyl 8- and 5-Nitro-1,4-Benzodioxane-2-Carboxylate

“…Indeed, many different preparative approaches have been developed to obtain them in unichiral form, ranging from enantioselective syntheses to any kind of racemate resolution and use of starting C3 synthetic units available from the "chiral pool" [5]. On the other hand, decoration of the benzene ring (Figure 1), a feature of benzodioxane derivatives often critically related to selectivity for biological receptor subtypes or agonist/antagonist profile [6,7], can only be accomplished using two alternative strategies: condensation of a C3 synthetic unit with benzene already bearing the desired substituents or the introduction of the substituents of benzene into the preformed 2-substituted 1,4-benzodioxane. The two strategies are well exemplified by the recently reported condensation of ethyl 2,3-dibromopropionate with 3-methoxycatechol to give ethyl 5-and 8-methoxy-1,4-benzodioxane-2-carboxylate and Friedel-Craft acetylation of ethyl 1,4-benzodioxane-2-carboxylate to give ethyl 6-and 7-acetyl-1,4-benzodioxane-2carboxylate [8].…”