Bioisosteric replacement strategy for the synthesis of 1-azacyclic compounds with high affinity for the central nicotinic cholinergic receptors.
Bioisosteric replacement of the isoxazole heterocycle in (3-methyl-5-isoxazolyl)methylene-azacyclic compounds with pyridine, oxadiazole, or an acyl group resulted in ligands with high to moderate affinity for the central nicotinic cholinergic receptors (IC50 = 2.0 to IC50 > 1000 nM) labeled by [3H]methylcarbamylcholine. Additionally, further support of an important distance parameter for high-affinity nicotinic compounds has been provided.
Olesen
P H
PH
Health Care Discovery, Novo Nordisk A/S, Målov, Denmark. phol@novo.dk
Tønder
J E
JE
Hansen
J B
JB
Hansen
H C
HC
Rimvall
K
K
D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D011978:Receptors, Nicotinic / Q000187:drug effects*
D001372:Aza Compounds; D001643:Bridged Bicyclo Compounds; D011978:Receptors, Nicotinic