A structure-activity relationship study of the positive allosteric modulator LY2033298 at the M4 muscarinic acetylcholine receptor

Szabo, Monika; Huynh, Tracey; Valant, Celine; Lane, J Robert; Sexton, Patrick M; Christopoulos, Arthur; Capuano, Ben

Abstract

Positive allosteric modulators (PAMs) targeting the M4 muscarinic acetylcholine receptor (mAChR) offer greater sub-type selectivity and unique potential as central nervous system agents through their novel mode of action to traditional orthosteric ligands. In an attempt to elucidate the molecular determinants of allostery mediated by the exemplar thienopyridine M4 mAChR PAM, LY2033298, we report herein a systematic structure–activity relationship (SAR) study investigating different linkage points, halogen replacements to examine size and electronic effects, and different substitution combinations on the thienopyridine scaffold. We applied an operational model of allosterism to determine values of functional affinity (KB), cooperativity (αβ) and intrinsic agonism (τB) for all compounds.

Citation

Szabo, M., Huynh, T., Valant, C., Lane, J. R., Sexton, P. M., Christopoulos, A., & Capuano, B. (2015). A structure-activity relationship study of the positive allosteric modulator LY2033298 at the M4 muscarinic acetylcholine receptor. MedChemComm, 6(11), 1998-2003. https://doi.org/10.1039/C5MD00334B

• Journal Article Type: Article
• Acceptance Date: Sep 28, 2015
• Online Publication Date: Sep 30, 2015
• Publication Date: Nov 1, 2015
• Deposit Date: Apr 22, 2020
• Journal: MedChemComm
• Print ISSN: 2040-2503
• Publisher: Royal Society of Chemistry
• Peer Reviewed: Peer Reviewed
• Volume: 6
• Issue: 11
• Pages: 1998-2003
• DOI: https://doi.org/10.1039/C5MD00334B
• Public URL: http://xlink.rsc.org/?DOI=C5MD00334B
• Publisher URL: https://pubs.rsc.org/en/content/articlelanding/2015/md/c5md00334b#!divAbstract