2-(Arylmethyl)-3-substituted quinuclidines as selective alpha 7 nicotinic receptor ligands |
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Authors: | Mazurov Anatoly Klucik Jozef Miao Lan Phillips Teresa Y Seamans Angela Schmitt Jeffrey D Hauser Terry A Johnson Raymond T Miller Craig |
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Institution: | Targacept, Inc., Medicinal Chemistry, 200 East First Street, Suite 300, Winston-Salem, NC 27101, USA. anatoly.mazurov@targacept.com |
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Abstract: | A series of 2-(arylmethyl)-3-substituted quinuclidines was developed as alpha7 neuronal nicotinic acetylcholine receptor (nAChR) agonists based on a putative pharmacophore model. The series is highly selective for the alpha7 over other nAChRs (e.g., the alpha4beta2 of the CNS, and the muscle and ganglionic subtypes) and is functionally tunable at alpha7. One member of the series, (+)-N-(1-azabicyclo2.2.2]oct-3-yl)benzob]furan-2-carboxamide (+)-8l), has potent agonistic activity for the alpha7 nAChR (EC(50)=33nM, I(max)=1.0), at concentrations below those that result in desensitization. |
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