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Synthesis and SAR of a mGluR5 allosteric partial antagonist lead: unexpected modulation of pharmacology with slight structural modifications to a 5-(phenylethynyl)pyrimidine scaffold |
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| Authors: | Sharma Sameer Rodriguez Alice L Conn P Jeffrey Lindsley Craig W |
| Institution: | aDepartment of Pharmacology, Vanderbilt University Medical Center, 12415D MRBIV, Nashville, TN 37232, USA;bDepartment of Chemistry, Vanderbilt University Medical Center, Nashville, TN 37232, USA;cVanderbilt Program in Drug Discovery, Vanderbilt Institute of Chemical Biology, Nashville, TN 37232, USA;dChemical and Physical Biology Program, Vanderbilt University, Nashville, TN 37232, USA |
| Abstract: | This Letter describes the synthesis and SAR, developed through an iterative analogue library approach, of a mGluR5 allosteric partial antagonist lead based on a 5-(phenylethynyl)pyrimidine scaffold. With slight structural modifications to the distal phenyl ring, analogues demonstrated a range of pharmacological activities from mGluR5 partial antagonism to full antagonism/negative allosteric modulation to positive allosteric modulation. |
| Keywords: | Allosteric mGluR5 Partial antagonism Positive allosteric modulation Antagonist |
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