5-(2-Pyrrolidinyl)oxazolidinones and 2-(2-pyrrolidinyl)benzodioxanes: Synthesis of all the stereoisomers and α4β2 nicotinic affinity

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

“…Lastly, to prepare (R,S)-13 and (S,S)-13, which are described as an unresolved diastereomeric mixture, 29 the Boc protecting group of the secondary alcohols (R,S)-24 and (S,S)-24 was reduced to methyl. The 1 H NMR signal of the exocyclic methine of the resulting N-methylamino alcohols (R,S)-28 and (S,S)-28, whose configurations are known because they are derived from (R,S)-24 28 and (S,S)-24, was a quartet of doublets and a quintet, respectively, thus confirming the previous configurations assignments to 8 Table 1 together with those previously reported for (S)-1, 23 (R,S)-2, 25 and (R,S)-3. 22 On the basis of their α4β2 affinity, two groups of compounds can be distinguished.…”

“…Consistent with such results, our previous docking analysis showed similar interactions of the protonated pyrrolidine ring and of the benzodioxane substructure of (R,S)-2 and (R,S)-3 with α4 and β2 amino acid residues of the α4β2-nAChR binding pocket and, only for (R,S)-3, additional H-bonds between the 7-hydroxyl and two serines, Ser(111) and Ser(115) of the β2 subunit. 22,25 These additional bonds would be responsible for the increased potency and the β2 selectivity, while substitutions other than OH are found unproductive or deleterious apparently because only small substituents can be accepted at benzodioxane 7-position. 22 Compared to our pyrrolidinylbenzodioxanes, nicotinoids with a flexible oxymethylene bridge between the aromatic where I is the peak current amplitude induced by the agonist at concentration C, I max is the maximum response of the cell, nH the Hill coefficient, and EC 50 the concentration at which a half-maximum response is induced.…”

“…22 The only one in a series of analogues with different 7-substituents to have nanomolar binding affinity, (R,S)-3 resulted from a SAR study on 2-(1′-methyl-2′-pyrrolidinyl)-1,4-benzodioxane (2), an α4β2-nAChR ligand with moderate submicromolar affinity when S configured at the pyrrolidine stereocenter, in turn designed by rigidifying the phenoxymethylene portion of the known nicotinic agonist Nmethylprolinol phenyl ether 1 23 in the 1,4-benzodioxane system (Chart 2). 24,25 The considerable enhancement of α4β2 affinity caused by the 7-OH substituent at the benzodioxane nucleus and the high α4β2 versus α3β4 functional selectivity of (R,S)-3 prompted us to study the effect of such a beneficial substitution also at the meta position of the conformationally free parent compound of 3, namely, the prolinol phenyl ether 1, and of two semirigid analogues of 3, the prolinol 2-methoxyphenyl ether 7 and the α-methylprolinol phenyl ether 8 (Chart 3). In addition to the phenyl ethers 1, 7, and 8 and their respective metahydroxylated analogues 4, 9, and 10, we also considered the azetidinyl analogue 5 of 4 and the pyridines 6, 11, 12, and 13, which are isosteres of 4, 7, and 8 (Chart 3).…”

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

“…In 2009, we reported the synthesis of all the stereoisomers of 2-(2-pyrrolidinyl) benzodioxanes ( 21) and evaluated their binding affinities at the α4β2 nAChRs (Table 4) [24]. 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.…”

“…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].…”