Novel pyridyl ring C5 substituted analogues of epibatidine and 3-(1-methyl-2(S)-pyrrolidinylmethoxy)pyridine (A-84543) as highly selective agents for neuronal nicotinic acetylcholine receptors containing beta2 subunits.
Introduction of a hydrophobic or hydrogen-bonding alkynyl group into the C5 position of the pyridyl ring of epibatidine and A-84543 significantly increased the selectivity for neuronal nicotinic acetylcholine receptors (nAChRs) containing beta2 subunits over nAChRs containing beta4 subunits (K(i) ratio up to 92000-fold). Our data indicate that the extracellular domains of the nAChRs are sufficiently different to allow for the design of novel ligands with high affinity and selectivity for the nAChR subtypes.
Wei
Zhi-Liang
ZL
Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, USA.
Xiao
Yingxian
Y
Yuan
Hongbin
H
Baydyuk
Maryna
M
Petukhov
Pavel A
PA
Musachio
John L
JL
Kellar
Kenneth J
KJ
Kozikowski
Alan P
AP
D000818:Animals; D001665:Binding Sites; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D009474:Neurons / Q000378:metabolism*; D021122:Protein Subunits / Q000737:chemistry / Q000187:drug effects; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000187:drug effects*
C116733:3-(2-(pyrrolidinyl)methoxy)pyridine; D019086:Bridged Bicyclo Compounds, Heterocyclic; D008024:Ligands; D021122:Protein Subunits; D011725:Pyridines; D011759:Pyrrolidines; D011978:Receptors, Nicotinic; C082748:epibatidine