AF710B

AF710B (ANAVEX 3-71) is a highly potent and selective allosteric agonist of the M1 subtype of the muscarinic acetylcholine receptor (M1 mAChR) and a concurrent agonist of the sigma-1 receptor (sigma-1R), first reported by Fisher et al. (2016) in Neurodegenerative Diseases as a next-generation candidate for cognitive enhancement and disease modification in Alzheimer's disease [1]. The compound emerged from a decades-long medicinal chemistry program at the Israel Institute for Biological Research (IIBR) that previously produced the orthosteric M1 agonists AF102B (cevimeline, approved for Sjogren's syndrome), AF267B, and AF292, each of which demonstrated procognitive and anti-amyloidogenic activity in preclinical and early clinical settings but was limited by insufficient M1 selectivity, dose-limiting cholinergic adverse events, or both. AF710B was designed to overcome these limitations through an allosteric mechanism of M1 receptor engagement: at nanomolar concentrations the compound potentiates the binding and efficacy of the endogenous agonist acetylcholine (and of the reference orthosteric agonist carbachol) at the M1 receptor, amplifying downstream signaling through phospho-ERK1/2 and phospho-CREB pathways without producing the gastrointestinal and cardiovascular cholinergic toxicity that constrained the earlier orthosteric series [1, 2]. Selectivity screening at 10 micromolar against 83 additional G-protein-coupled receptors, ion channels, and transporters produced no significant off-target hits, establishing a pharmacological selectivity profile substantially cleaner than that of xanomeline and other earlier M1-preferring agonists [1]. The sigma-1 receptor agonism adds a second, mechanistically independent neuroprotective axis. Sigma-1R is an endoplasmic reticulum chaperone protein concentrated at the mitochondria-associated endoplasmic reticulum membrane (MAM), where it regulates calcium transfer between the endoplasmic reticulum and mitochondria, modulates the unfolded protein response, and activates anti-inflammatory and antiapoptotic signaling cascades [3, 4]. Activation of sigma-1R by AF710B has been linked to rescue of mushroom spine loss in presenilin-1 knock-in and APP knock-in neuronal cultures, reduction of neuroinflammatory markers, and normalization of brain-derived neurotrophic factor (BDNF) signaling in transgenic models [1, 5]. In the seminal Fisher et al. (2016) study, AF710B administered to female 3xTg-AD mice at 10 micrograms per kilogram intraperitoneally daily for two months mitigated cognitive impairment in the Morris water maze and reduced BACE1 expression, GSK3-beta activity, p25/CDK5 levels, neuroinflammation, soluble and insoluble amyloid-beta 40 and 42, amyloid plaques, and phosphorylated tau pathology [1]. A subsequent study by Hall et al. (2018) in Alzheimer's and Dementia extended these findings to the McGill-R-Thy1-APP transgenic rat model, demonstrating that chronic oral AF710B at 10 micrograms per kilogram daily for 4.5 months in 13-month-old (post-plaque) rats reversed cognitive deficits, reduced hippocampal amyloid plaque burden and cortical amyloid-beta 40 and 42 levels, decreased neuroinflammatory markers, increased cerebrospinal fluid amyloid clearance, and elevated the synaptic marker synaptophysin [6]. The disease-modifying character of the effect was underscored by its persistence through a five-week drug washout period following treatment cessation. A third study (Bhatt et al., 2024, Neurobiology of Aging) confirmed that early treatment with AF710B in the same rat model prevented cognitive decline when treatment was initiated before overt plaque deposition [7]. Anavex Life Sciences Corporation acquired exclusive worldwide rights to the AF710B intellectual property in 2014 and advanced the compound under the designation ANAVEX 3-71 through a first-in-human Phase 1 single ascending dose study in 42 healthy volunteers (2020 to 2021), which demonstrated safety and tolerability at oral doses of 5 to 200 mg with no serious adverse events, no clinically significant electrocardiogram changes, and linear, dose-proportional pharmacokinetics with a mean terminal elimination half-life of approximately 3.56 hours [8, 9]. A Phase 1b study subsequently confirmed the bioavailability of a once-daily oral tablet formulation. In 2024, Anavex initiated a placebo-controlled Phase 2 study (ANAVEX3-71-SZ-001) in adults with schizophrenia, and in October 2025 reported positive topline results demonstrating safety, tolerability, reduction in the neuroinflammatory biomarker glial fibrillary acidic protein (GFAP), and encouraging trends in EEG and event-related potential biomarkers [10, 11]. The compound has received orphan drug designation from the FDA for frontotemporal dementia. No registration-enabling Phase 3 trial has been completed for any indication as of the most recent monograph revision. This monograph documents the chemistry, synthesis, dual-receptor pharmacology, pharmacokinetics, preclinical and clinical evidence, sourcing and handling considerations, stack interactions, adverse-event profile, and a structured comparative assessment of AF710B against five muscarinic and sigma-1 receptor candidates on five competency standards.