title: 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.
authors.affiliation: Laboratory of Design, Synthesis and Study of Biologically Active Heterocycles (HeteroBioLab), Department of Pharmaceutical Sciences, University of Florence, via Ugo Schiff 6, I-50019 Sesto Fiorentino, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Guandalini
authors.forename: Monica
authors.initials: M
authors.lastname: Norcini
authors.forename: Katia
authors.initials: K
authors.lastname: Varani
authors.forename: Marco
authors.initials: M
authors.lastname: Pistolozzi
authors.forename: Cecilia
authors.initials: C
authors.lastname: Gotti
authors.forename: Carla
authors.initials: C
authors.lastname: Bazzicalupi
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Martini
authors.forename: Silvia
authors.initials: S
authors.lastname: Dei
authors.forename: Dina
authors.initials: D
authors.lastname: Manetti
authors.forename: Serena
authors.initials: S
authors.lastname: Scapecchi
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Teodori
authors.forename: Carlo
authors.initials: C
authors.lastname: Bertucci
authors.forename: Carla
authors.initials: C
authors.lastname: Ghelardini
authors.forename: Maria Novella
authors.initials: MN
authors.lastname: Romanelli
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D018360:Crystallography, X-Ray; D015195:Drug Design; D008024:Ligands; D051379:Mice; D008968:Molecular Conformation; D010147:Pain Measurement; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D000700:Analgesics; C579166:Chrna7 protein, mouse; C579165:Chrna7 protein, rat; D008024:Ligands; C524185:N,N,N-trimethyl-4-(quinolin-6-yl)but-3-en-1-ammonium; C524184:N,N,N-trimethyl-4-(quinolin-6-yl)but-3-yn-1-ammonium; D011804:Quinolines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C403531:nicotinic receptor alpha4beta2