Challenges in the development of mGluR5 positive allosteric modulators: The discovery of CPPHA

This Letter describes, for the first time, the synthesis and SAR, developed through an iterative analog library approach, that led to the discovery of the positive allosteric modulator (PAM) of the metabotropic glutamate receptor mGluR5 CPPHA. Binding to a unique allosteric binding site distinct fro...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2007-03, Vol.17 (5), p.1386-1391
Hauptverfasser:	Zhao, Zhijian, Wisnoski, David D., O’Brien, Julie A., Lemaire, Wei, Williams, David L., Jacobson, Marlene A., Wittman, Marion, Ha, Sookhee N., Schaffhauser, Herve, Sur, Cyrille, Pettibone, Doug J., Duggan, Mark E., Conn, P. Jeffrey, Hartman, George D., Lindsley, Craig W.
Format:	Artikel
Sprache:	eng
Schlagworte:	Allosteric modulator Allosteric Regulation Allosteric Site Animals Benzamides - chemistry Benzamides - pharmacology Biological and medical sciences Glutamatergic system (aspartate and other excitatory aminoacids) Humans Medical sciences MGluR5 Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Pharmacology. Drug treatments Phthalimides - chemistry Phthalimides - pharmacology Potentiation Rats Receptor, Metabotropic Glutamate 5 Receptors, Metabotropic Glutamate - drug effects Structure-Activity Relationship
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Beschreibung
Zusammenfassung:	This Letter describes, for the first time, the synthesis and SAR, developed through an iterative analog library approach, that led to the discovery of the positive allosteric modulator (PAM) of the metabotropic glutamate receptor mGluR5 CPPHA. Binding to a unique allosteric binding site distinct from other mGluR5 PAMs, CPPHA has been the focus of numerous pharmacology studies by several laboratories.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2006.11.081