Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10596439 | Bioorganic & Medicinal Chemistry Letters | 2012 | 6 Pages |
Abstract
A library of N-substituted 4-azahexacyclo[5.4.1.02,6.03,10.05,9.08,11]dodecan-3-ols (AHDs) was synthesized and subjected to competition binding assays at Ï1 and Ï2 receptors, as well as off-target screening of representative members at 44 other common central nervous system (CNS) receptors, transporters, and ion channels. Excluding 3 low affinity analogs, 31 ligands demonstrated nanomolar Ki values for either Ï receptor subtype. Several selective Ï1 and Ï2 ligands were discovered, with selectivities of up to 29.6 times for Ï1 and 52.4 times for Ï2, as well as several high affinity, subtype non-selective ligands. The diversity of structures and Ï1 affinities of the ligands allowed the generation of a Ï1 receptor pharmacophore that will enable the rational design of increasingly selective and potent Ï1 ligands for probing Ï1 receptor function.
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Authors
Samuel D. Banister, Miral Manoli, Munikumar Reddy Doddareddy, David E. Hibbs, Michael Kassiou,