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

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 α7* nicotinic receptor enantioselectivity is inverted with respect to the α4β2* 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 Å, interact with the α4β2* nicotinic receptor with Ki in the μM range; compound 3c shows preference for the α7* subtype.