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Continued optimization of the MLPCN probe ML071 into highly potent agonists of the hM1 muscarinic acetylcholine receptor |
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| Authors: | Melancon Bruce J Gogliotti Rocco D Tarr James C Saleh Sam A Chauder Brian A Lebois Evan P Cho Hyekyung P Utley Thomas J Sheffler Douglas J Bridges Thomas M Morrison Ryan D Daniels J Scott Niswender Colleen M Conn P Jeffrey Lindsley Craig W Wood Michael R |
| Institution: | Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA. |
| Abstract: | This Letter describes the continued optimization of the MLPCN probe molecule ML071. After introducing numerous cyclic constraints and novel substitutions throughout the parent structure, we produced a number of more highly potent agonists of the M(1) mACh receptor. While many novel agonists demonstrated a promising ability to increase soluble APPα release, further characterization indicated they may be functioning as bitopic agonists. These results and the implications of a bitopic mode of action are presented. |
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