RESEARCH MONOGRAPH · KDC-MN-1354

AVL-3288

May 10, 2026 Kodiac biolabs Research Revised May 19, 2026 3 min read

Our opinion on this compound

66/100

Positive allosteric modulator strategy for alpha-7. Likely where the receptor's clinical future actually lives

AVL-3288 (also called UCI-4083, originally Univ. of California Irvine chemistry) is a type I positive allosteric modulator (PAM) of the alpha-7 nAChR, and it represents what we think is the most promising strategic angle on this receptor. The encenicline-bradanicline-GTS-21 era was about direct agonists, and the underwhelming clinical outcomes pushed the field toward PAMs as a fundamentally different way of engaging alpha-7.

The PAM logic for alpha-7 is good pharmacology. Direct agonists drive the receptor through its activation cycle on their own schedule, which often means flooding the system and desensitizing the receptor. A PAM doesnt activate the receptor on its own, it amplifies the response to endogenous acetylcholine in spatial and temporal patterns that the brain itself dictates. The type I distinction (preserves desensitization kinetics) versus type II (delays desensitization) matters because type II PAMs at alpha-7 have a calcium-overload problem that's been a real safety concern. AVL-3288's type I profile is the safer of the two strategies.

The phase 1 data in healthy volunteers showed a clean tolerability profile, dose-proportional PK, and EEG effects consistent with target engagement. The phase 2 schizophrenia cognition trial run by UCI showed mixed results, the kind of phase 2 where the cognition signal is suggestive but not definitive. The overall development program has been at academic-grade pace rather than industry-grade pace.

What we like is that the receptor pharmacology argument for PAMs is genuinely strong, and AVL-3288 is the best-characterized type I alpha-7 PAM in human studies. If alpha-7 is going to have a clinical future, it probably comes through PAM development, and AVL-3288 is the closest thing to a proof-of-concept tool we have.

What we hedge on is the limited human efficacy data. Phase 2 mixed signals plus a slow development cadence means we dont have the kind of solid clinical readout that would let us say the PAM strategy works in humans. The mechanism makes sense, the safety looks fine, the efficacy story is still being written.

Sourcing is small-molecule with published chemistry. NMR, HPLC, and pharmacological validation by alpha-7 patch-clamp or calcium flux is the gold standard for verification. Most research suppliers will provide NMR and HPLC but functional validation is rare.

For alpha-7 PAM research this is a real tool. We think this is where the receptor's clinical story actually progresses.

Evidence: 45
Mechanism: 82
Reliability: 65
Safety: 78
Sourcing: 65
Value: 65
Signal: 60
Staying power: 65

Type I positive allosteric modulator of the alpha-7 nicotinic acetylcholine receptor

An isoxazole-acrylamide chemical entity originally developed at the University of California Irvine as compound CCMI and licensed through multiple owners to Anvylic Therapeutics, representing the most mechanistically distinct alpha-7 nicotinic candidate in clinical development through its Type I positive allosteric modulator mechanism that preserves the spatiotemporal specificity of endogenous cholinergic neurotransmission.

Abstract

AVL-3288 (also known as UCI-4083, CCMI, Anvylic-3288, and XY-4083) is a small-molecule, orally bioavailable Type I positive allosteric modulator (PAM) of the alpha-7 subtype of the neuronal nicotinic acetylcholine receptor. The compound is mechanistically distinct from the partial-agonist (tropisetron, encenicline, GTS-21) and full-agonist (bradanicline, PHA-543613) classes that have dominated alpha-7 nicotinic receptor drug development. Type I PAMs bind the alpha-7 receptor at an allosteric site distinct from the orthosteric (acetylcholine) binding site, do not directly activate the receptor in the absence of agonist, and enhance the potency and efficacy of endogenous acetylcholine signaling at the receptor. Critically, Type I PAMs preserve the rapid desensitization kinetics of the alpha-7 channel and therefore preserve the spatiotemporal specificity of cholinergic neurotransmission. The compound was originated at the University of California Irvine in the laboratory of Kelvin Gee in the early 2000s and licensed through multiple commercial owners to Anvylic Therapeutics. Phase 1a in 21 healthy non-smokers and Phase 1b in 24 schizophrenia outpatients at 10 to 30 milligrams produced safety, dose-proportional pharmacokinetics, and exploratory cognitive and P50 auditory gating biomarker signals. AVL-3288 represents the most mechanistically novel of the alpha-7 nicotinic receptor candidates and is the principal contemporary alternative therapeutic concept for the alpha-7 nicotinic target.

Mechanism of action

Type I positive allosteric modulation of the alpha-7 nicotinic acetylcholine receptor. Binds an allosteric site distinct from the orthosteric (acetylcholine) site; does not directly activate the receptor in absence of agonist; enhances potency and efficacy of endogenous acetylcholine signaling. Preserves rapid desensitization kinetics of the alpha-7 channel (Type I PAM criterion), preserving spatiotemporal specificity of cholinergic neurotransmission.

Reported research dose ranges

Phase 1a single oral doses 5, 10, 30 mg in healthy volunteers. Phase 1b 10 or 30 mg per oral administration once daily for 5 days in schizophrenia outpatients. Research applications: in vitro 0.1-30 micromolar; rodent in vivo 1-30 mg/kg.

Selected references

Ng HJ et al. Nootropic alpha-7 nicotinic receptor allosteric modulator derived from GABAA receptor modulators. Proc Natl Acad Sci USA. 2007;104(19):8059-8064.
Gee KW et al. First in human trial of a type I positive allosteric modulator of alpha-7 nicotinic receptors: pharmacokinetics, safety, and evidence for neurocognitive effect of AVL-3288. J Psychopharmacol. 2017;31(4):434-441.
Freedman R et al. Double blind, two dose, randomized, placebo-controlled, cross-over clinical trial of the positive allosteric modulator at the alpha-7 nicotinic cholinergic receptor AVL-3288 in schizophrenia patients. Neuropsychopharmacology. 2020;45(8):1339-1346.
Gronlien JH et al. Distinct profiles of alpha-7 nAChR positive allosteric modulation revealed by structurally diverse chemotypes. Mol Pharmacol. 2007;72(3):715-724.
Williams DK et al. Positive allosteric modulators as an approach to nicotinic acetylcholine receptor-targeted therapeutics: advantages and limitations. Biochem Pharmacol. 2011;82(8):915-930.

Read the full monograph

The full reference document covers compound identification with chemistry and synthesis, discovery and developmental history, mechanism of action across molecular targets with quantitative receptor pharmacology, comprehensive pharmacokinetics, indication-by-indication clinical evidence base, reported research dose ranges, sourcing and quality verification, reconstitution and handling, stack interaction considerations, adverse event signal, and a structured comparative assessment of five alpha-7 nicotinic acetylcholine receptor candidates judged against five competency standards. Embedded inline below; download for offline reading.

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AVL-3288

Abstract

Mechanism of action

Reported research dose ranges

Selected references

Read the full monograph

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Abstract

Mechanism of action

Reported research dose ranges

Selected references

Read the full monograph

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