Design, Synthesis, and Preliminary Pharmacological Evaluation of New Quinoline Derivatives as Nicotinic Ligands

Abstract

A series of nicotinic ligands, carrying a quinoline nucleus, and characterized by a pharmacophoric distance between the quinoline nitrogen (H-bond acceptor) and the cationic nitrogen atoms higher than that proposed in the classical pharmacophoric models, have been synthesized and tested for their affinity for the central nicotinic receptor. The enantiomers of the nicotine analogue 1-methyl-2-pyrrolidinyl-6-quinoline and of its methiodide display enantioselectivity in binding studies, but not when tested in vivo; on alpha7* nicotinic receptor enantioselectivity is inverted with respect to the alpha4beta2* subtype. N,N,N-Trimethyl-4-(quinolin-6-yl)but-3-yn-1-ammonium iodide (3c) and trans-N,N,N-trimethyl-4-(quinolin-6-yl)but-3-en-1-ammonium iodide (4c), showing pharmacophoric distances in the range 8.5-10.4 A, interact with the alpha4beta2* nicotinic receptor with Ki in the microM range; compound 3c shows preference for the alpha7* subtype.

Central Nicotinic Receptors: Structure, Function, Ligands, and Therapeutic Potential

“…[69] These compounds behave as nicotinic agonists in the hot-plate test on mice when injected i.c.v. [70] Compounds 9 were obtained by optimization of 10 a (R = NMe 2 ) and the methiodide 10 b (R = NMe 3 I), which were designed through a 3D- . Their isomers in position 5 or 7 were completely devoid of affinity.…”

Synthesis and Applications of Asymmetric Catalysis Using Chiral Ligands Containing Quinoline Motifs

“…[5][6][7][8][9][10][11] Moreover, many quinoline derivatives exhibiting significant biological activities have been isolated from plants or systematically designed and synthesized. [12][13] Quinolines and their derivatives have been labelled as "Privileged Scaffolds" owing to their prevalent existence in natural and synthetic molecules that exhibit notable applications in pharmacological, agrochemical and electronic industries [14][15][16][17][18][19][20][21][22][23][24] (Figure 1).…”

“…Quinolines and their derivatives have been labeled as ‘privileged scaffolds’ owing to their prevalent existence in natural and synthetic molecules that exhibit notable applications in pharmacological, agrochemical, and electronic industries (Figure 1 ). 14 15 16 17 18 19 20 21 22 23 24…”

Simple Chiral Pyrrolidine–Pyridine‐Based Catalysts for Highly Enantioselective Michael Addition to Nitro Olefins

“…A series of pyrrolidine–pyridine catalysts 3 were prepared from the “chiral pool” by using N ‐Boc‐ L ‐prolinol as the starting material 9. The synthetic procedures were quite straightforward; N ‐Boc‐ L ‐prolinol was coupled with bromopyridine reagents and then treated with TFA in CH 2 Cl 2 to afford the product (for example, 3a ) in 65 % total yield from N ‐Boc‐ L ‐prolinol (Scheme ) 10…”