Chemistry and Pharmacology of a Series of Unichiral Analogues of 2-(2-Pyrrolidinyl)-1,4-benzodioxane, Prolinol Phenyl Ether, and Prolinol 3-Pyridyl Ether Designed as α4β2-Nicotinic Acetylcholine Receptor Agonists

Abstract

Some unichiral analogues of 2R,2'S-2-(1'-methyl-2'-pyrrolidinyl)-7-hydroxy-1,4-benzodioxane, a potent and selective α4β2-nAChR partial agonist, were designed by opening dioxane and replacing hydroxyl carbon with nitrogen. The resulting 3-pyridyl and m-hydroxyphenyl ethers have high α4β2 affinity and good subtype selectivity, which get lost if OH is removed from phenyl or the position of pyridine nitrogen is changed. High α4β2 affinity and selectivity are also attained by meta hydroxylating the 3-pyridyl and the phenyl ethers of (S)-N-methylprolinol and the phenyl ether of (S)-2-azetidinemethanol, known α4β2 agonists, although the interaction mode of the aryloxymethylene substructure cannot be assimilated to that of benzodioxane. Indeed, the α4β2 and α3β4 functional tests well differentiate behaviors that the binding tests homologize: both the 3-hydroxyphenyl and the 5-hydroxy-3-pyridyl ether of N-methylprolinol are α4β2 full agonists, but only the latter is highly α4β2/α3β4 selective, while potent and selective partial α4β2 agonism characterizes the hydroxybenzodioxane derivative and its two opened semirigid analogues.

Minimal Structural Changes Determine Full and Partial Nicotinic Receptor Agonist Activity for Nicotine Analogues

“…Thus, the halogenated compounds (3 and 4) exhibited a similar affinity as compared to the unsubstituted derivative 1, whereas the introduction of an amino group at this position produced a clear increase of affinity. This effect has been reported with a hydroxyl analogue of compound 2, where the meta-hydroxyl position increases its affinity [23]. This might be due to the amino group, with donor/acceptor properties, being able to form hydrogen bridge(s) with some residues into the agonist binding site of the receptor.…”

“…In this regard and based on previous theoretical, ethical, and experimental reports [22,23,24], we have designed and synthesized a small series of known and novel compounds, based on the nicotine structure, in order to modulate both their affinity and efficacy for α4β2 nAChRs. Thus, the pyridine moiety of nicotine was modified by moving the nitrogen atom outside of the ring, which either maintains the amino group or changes it by a halogen atom such as chloro or bromo.…”

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

“…Analysis of α4β2 and α3β4 Affinity, Activity, and Selectivity Data from the Literature (S)-nicotine (Figure 2), the most known pyrrolidine-based ligand of the nAChRs, is a competitive full agonist at all the nicotinic subtypes, with preference at the heteromeric α2-6and β2-4-containing subtypes rather than to homomeric α7 and heteromeric α9α10 receptors. Particularly, (S)-nicotine is a nanomolar binder at the α4β2 subtype (K i = 2 nM at human α4β2 [34], K i = 4 nM at rat brain homogenates [32], and K i = 10 nM at rat α4β2 [35]), while it only has submicromolar affinity at the α3β4 subtype (K i = 261 nM at human α3β4 [32] and K i = 440 nM at rat α3β4 [35]), with an approximate α4β2 vs. α3β4 selectivity ratio (defined as K i (α3β4)/K i (α4β2)) of 65 times [32]. These values have been determined in [ 3 H]-epibatidine competition binding experiments and are in the same range of others reported in the literature [36,37].…”

“…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.…”

How do reaction conditions affect the enantiopure synthesis of 2‐substituted‐1,4‐benzodioxane derivatives?

“…The 1,4‐benzodioxane scaffold is a common building block of several biologically active molecules, acting towards a wide variety of pharmacological targets. The adrenergic, the catecholaminergic, and the dopaminergic systems are the most significant areas of interest in which they are involved in.…”