Rigidified acetylcholine mimics: conformational requirements for binding to neuronal nicotinic receptors.
Rigidified derivatives have been designed and synthesized assuming the g+t conformer of acetylcholine (N-C-C-O=+60 degrees, C-C-O-C=180 degrees ) as active conformation for binding to cytisine sensitive neuronal nicotinic receptors. The SAR of the compounds evaluated, along with those of more flexible analogues, support the g+t conformer hypothesis and highlight the stringent steric limitation of this nicotinic receptor sub-type. Compound 3e has low microM affinity for cytisine sensitive nicotinic receptor binding sites while being selective with regard to the alpha-bungarotoxin sensitive subclass. We also report few compounds with microM affinity for the alpha-bungarotoxin sensitive subclass.
Villeneuve
Gérald
G
Département de Chimie, Université de Sherbrooke, 2500 boulevard de l'Université, Sherbrooke, Québec, Canada J1K 2R1.
Cécyre
Danielle
D
Lejeune
Hélène
H
Drouin
Marc
M
Lan
Ruoxi
R
Quirion
Rémi
R
D000109:Acetylcholine / Q000737:chemistry* / Q000378:metabolism; D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D001392:Azocines / Q000494:pharmacology; D002038:Bungarotoxins / Q000494:pharmacology; D015195:Drug Design; D008401:Gas Chromatography-Mass Spectrometry; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D018716:Molecular Mimicry; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism; D011807:Quinolizines / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects*; D013329:Structure-Activity Relationship; D000093843:Quinolizidine Alkaloids
D000109:Acetylcholine; D000470:Alkaloids; D001392:Azocines; D002038:Bungarotoxins; D007202:Indicators and Reagents; D011807:Quinolizines; D011978:Receptors, Nicotinic; C004712:cytisine; D000093843:Quinolizidine Alkaloids