Discovery of structurally distinct tricyclic M4 positive allosteric modulator (PAM) chemotypes |
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| Institution: | 1. The Molecular Psychiatry Laboratory, The Florey Institute for Neuroscience and Mental Health, Parkville, Victoria 3052, Australia;2. Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, Victoria 3010, Australia |
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| Abstract: | This Letter details our efforts to develop new M4 PAM scaffolds with improved pharmacological properties. This endeavor involved replacing the 3,4-dimethylpyridazine core with two novel cores: a 2,3-dimethyl-2H-indazole-5-carboxamide core or a 1-methyl-1H-benzod]1,2,3]triazole-6-carboxamide core. Due to shallow SAR, these cores were further evolved into two unique tricyclic cores: an 8,9-dimethyl-8H-pyrazolo3,4-h]quinazoline core and an 1-methyl-1H-1,2,3]triazolo4,5-h]quinazoline core. Both tricyclic cores displayed low nanomolar potency against both human and rat M4. |
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| Keywords: | Muscarinic acetylcholine receptor Positive allosteric modulator (PAM) Structure activity relationship (SAR) |
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