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

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 (K_B), cooperativity (αβ) and intrinsic agonism (τ_B) for all compounds.