ANAVEX 3-71

ANAVEX 3-71 (development code AF710B; CAS 1235733-73-9) is a synthetic spirocyclic thiadiazine-piperidine compound and a dual allosteric agonist at the M1 subtype of the muscarinic acetylcholine receptor and the sigma-1 receptor (SIGMAR1). The compound was invented by Abraham Fisher at the Israel Institute for Biological Research (IIBR) in Ness Ziona, Israel, as the fourth generation of a series of cholinergic agonists (AF102B, AF267B, AF292, AF710B) with progressively greater selectivity and allosteric character at the M1 muscarinic receptor. ANAVEX 3-71 emerged from high-throughput receptogram profiling as a compound with sub-nanomolar allosteric binding affinity at M1 muscarinic receptors (approximately 0.05 nM) and nanomolar affinity at the sigma-1 receptor (Ki approximately 1.3 nM), with no agonistic activity at M2 through M5 muscarinic subtypes, no significant binding at alpha-4-beta-2 or alpha-7 nicotinic receptors, and a clean off-target profile across 83 additional G-protein-coupled receptors, ion channels, and transporters screened at 10 micromolar. The preclinical pharmacology of ANAVEX 3-71 has been characterized principally in three studies using transgenic rodent models of Alzheimer's disease. Fisher et al. (2016) reported that AF710B at 10 micrograms per kilogram in the published literature intraperitoneally for two months in 3xTg-AD mice reversed cognitive deficits in the Morris water maze, decreased BACE1, GSK3-beta activity, and tau phosphorylation at multiple epitopes (AT180, AT270, PHF-1), reduced soluble and insoluble amyloid-beta 40 and 42, and rescued mushroom dendritic spine loss in hippocampal neuronal cultures at 30 nanomolar. Hall et al. (2018) extended these findings to McGill-R-Thy1-APP transgenic rats, demonstrating that oral treatment at 10 micrograms per kilogram in the published literature for 4.5 months at 13 months of age (postplaque) reverted cognitive deficits, reduced amyloid pathology and neuroinflammation, and increased cerebrospinal fluid amyloid clearance, with effects maintained following a 5-week treatment interruption consistent with disease-modifying rather than symptomatic activity. Orciani et al. (2023) demonstrated that early (preplaque, 7 months of age) treatment at the same dose for 7 months prevented cognitive impairment, reduced hippocampal plaque burden and cortical amyloid-beta peptides, attenuated microglial and astrocytic neuroinflammation, and rescued pro-BDNF to mature BDNF conversion, with effects persisting through a 4-week washout. Human pharmacokinetics characterized in a Phase 1 single ascending dose study (NCT04442945; 36 healthy volunteers; 5 to 200 mg) demonstrate linear, dose-proportional, and time-invariant pharmacokinetics with a mean apparent terminal elimination half-life of 3.56 hours for the parent compound and 6.59 hours for the M8 metabolite. No clinically relevant effects on QTc or other electrocardiographic parameters were observed across the full studied dose range. Food had no effect on the pharmacokinetics of ANAVEX 3-71 or its M8 metabolite. Clinical development is ongoing across multiple indications. A Phase 2 study in schizophrenia (NCT06245213; 71 subjects) reported dose-dependent improvements in electroencephalographic biomarkers and favorable safety and tolerability with no serious treatment-emergent adverse events. A modified-release oral tablet enabling once-daily dosing was successfully developed in a Phase 1b study completed in October 2025. ANAVEX 3-71 is not approved by any regulatory authority and is supplied as a research-grade preparation. This monograph reviews the chemistry, dual-receptor pharmacology, preclinical pharmacology in transgenic Alzheimer's models, human pharmacokinetics, the clinical evidence base, sourcing and quality verification, handling considerations, interaction profile, adverse event signal, and a comparative assessment of five mechanistically related compounds against ANAVEX 3-71 on five competency standards.