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 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.
Guandalini
Luca
L
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.
Norcini
Monica
M
Varani
Katia
K
Pistolozzi
Marco
M
Gotti
Cecilia
C
Bazzicalupi
Carla
C
Martini
Elisabetta
E
Dei
Silvia
S
Manetti
Dina
D
Scapecchi
Serena
S
Teodori
Elisabetta
E
Bertucci
Carlo
C
Ghelardini
Carla
C
Romanelli
Maria Novella
MN
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
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