Synonym
AVL-3288; AVL 3288; AVL3288; XY-4083; XY 4083; XY4083; Anvylic-3288; UCI-4083; UCI4083; UCI 4083; CCMI.
IUPAC/Chemical Name
(Z)-3-(4-Chloroanilino)-N-(4-chlorophenyl)-2-(3-methylisoxazol-5-yl)prop-2-enamide
InChi Key
VMAKIACTLSBBIY-BOPFTXTBSA-N
InChi Code
InChI=1S/C19H15Cl2N3O2/c1-12-10-18(26-24-12)17(11-22-15-6-2-13(20)3-7-15)19(25)23-16-8-4-14(21)5-9-16/h2-11,22H,1H3,(H,23,25)/b17-11-
SMILES Code
O=C(NC1=CC=C(Cl)C=C1)/C(C2=CC(C)=NO2)=C\NC3=CC=C(Cl)C=C3
Purity
>98% (or refer to the Certificate of Analysis)
Shipping Condition
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
Soluble in DMSO
Shelf Life
>2 years if stored properly
Drug Formulation
This drug may be formulated in DMSO
Stock Solution Storage
0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code
2934.99.9001
More Info
Nicotinic acetylcholine receptor (nAChR) agonists such as nicotine have been shown to enhance cognitive performance, especially functions in the attention domain. Efforts have been made to develop similar compounds as therapeutic agents for disorders such as schizophrenia or Alzheimer's disease. Over the last two decades, drug development has invested into novel nAChR agonists. Effects have generally been in the expected direction, but tended to be of small magnitude. A potential way of increasing the effect size ceiling is by co-administering a nAChR positive allosteric modulator (PAM). PAMs generally do not activate the nAChR on their own but bind to a second, modulatory site and facilitate agonist-induced responses.
Biological target:
AVL-3288 is an allosteric modulator of the alpha7 nicotinic acetylcholine receptor (α7 nAChR).
In vivo activity:
Traumatic brain injury (TBI) is characterized by persistent hippocampal-dependent learning and memory deficits in contextual fear conditioning and the water maze task. To determine if AVL-3288 could rescue these cognitive deficits, animals were treated with AVL-3288 or vehicle at 30 min prior to cue and contextual fear conditioning (Fig 2). Since activation of α7 nAChRs converts short-term potentiation in hippocampal slices to LTP, animals were treated during training, but not during testing. No significant differences were observed in cue and contextual fear conditioning between sham animals treated with vehicle versus AVL-3288. In TBI animals, AVL-3288 significantly improved both cue and contextual fear conditioning when assessed 24 hr after training for recent recall (surgery x drug treatment interaction: cue F(1,36) = 4.29, p = 0.045; context F(1,36) = 8.32, p = 0.007). The effects on fear memory were persistent as shown by a significant improvement in remote recall assessed 1 month after training (surgery x drug treatment interaction: cue F(1,36) = 6.75, p = 0.013; context F(1,36) = 6.59, p = 0.015).
Reference: PLoS One. 2019 Oct 3;14(10):e0223180. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6776323/
Preparing Stock Solutions
The following data is based on the
product
molecular weight
388.25
Batch specific molecular weights may vary
from batch to batch
due to the degree of hydration, which will
affect the solvent
volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass |
1 mg |
5 mg |
10 mg |
| 1 mM |
1.15 mL |
5.76 mL |
11.51 mL |
| 5 mM |
0.23 mL |
1.15 mL |
2.3 mL |
| 10 mM |
0.12 mL |
0.58 mL |
1.15 mL |
| 50 mM |
0.02 mL |
0.12 mL |
0.23 mL |
Formulation protocol:
1. Titus DJ, Johnstone T, Johnson NH, London SH, Chapalamadugu M, Hogenkamp D, Gee KW, Atkins CM. Positive allosteric modulation of the α7 nicotinic acetylcholine receptor as a treatment for cognitive deficits after traumatic brain injury. PLoS One. 2019 Oct 3;14(10):e0223180. doi: 10.1371/journal.pone.0223180. PMID: 31581202; PMCID: PMC6776323.
In vivo protocol:
1. Titus DJ, Johnstone T, Johnson NH, London SH, Chapalamadugu M, Hogenkamp D, Gee KW, Atkins CM. Positive allosteric modulation of the α7 nicotinic acetylcholine receptor as a treatment for cognitive deficits after traumatic brain injury. PLoS One. 2019 Oct 3;14(10):e0223180. doi: 10.1371/journal.pone.0223180. PMID: 31581202; PMCID: PMC6776323.
1: Titus DJ, Johnstone T, Johnson NH, London SH, Chapalamadugu M, Hogenkamp D, Gee KW, Atkins CM. Positive allosteric modulation of the α7 nicotinic acetylcholine receptor as a treatment for cognitive deficits after traumatic brain injury. PLoS One. 2019 Oct 3;14(10):e0223180. doi: 10.1371/journal.pone.0223180. eCollection 2019. PubMed PMID: 31581202; PubMed Central PMCID: PMC6776323.
2: Yoshimura RF, Tran MB, Hogenkamp DJ, Ayala NL, Johnstone T, Dunnigan AJ, Gee TK, Gee KW. Allosteric modulation of nicotinic and GABA(A) receptor subtypes differentially modify autism-like behaviors in the BTBR mouse model. Neuropharmacology. 2017 Nov;126:38-47. doi: 10.1016/j.neuropharm.2017.08.029. Epub 2017 Aug 24. PubMed PMID: 28842344.
3: Gee KW, Olincy A, Kanner R, Johnson L, Hogenkamp D, Harris J, Tran M, Edmonds SA, Sauer W, Yoshimura R, Johnstone T, Freedman R. First in human trial of a type I positive allosteric modulator of alpha7-nicotinic acetylcholine receptors: Pharmacokinetics, safety, and evidence for neurocognitive effect of AVL-3288. J Psychopharmacol. 2017 Apr;31(4):434-441. doi: 10.1177/0269881117691590. Epub 2017 Feb 15. PubMed PMID: 28196430.
4: Wichern F, Jensen MM, Christensen DZ, Mikkelsen JD, Gondré-Lewis MC, Thomsen MS. Perinatal nicotine treatment induces transient increases in NACHO protein levels in the rat frontal cortex. Neuroscience. 2017 Mar 27;346:278-283. doi: 10.1016/j.neuroscience.2017.01.026. Epub 2017 Jan 25. PubMed PMID: 28131622; PubMed Central PMCID: PMC5360531.
5: Hashimoto K. Targeting of α7 Nicotinic Acetylcholine Receptors in the Treatment of Schizophrenia and the Use of Auditory Sensory Gating as a Translational Biomarker. Curr Pharm Des. 2015;21(26):3797-806. Review. PubMed PMID: 26044974; PubMed Central PMCID: PMC5024727.
6: Thomsen MS, Mikkelsen JD. Type I and II positive allosteric modulators differentially modulate agonist-induced up-regulation of α7 nicotinic acetylcholine receptors. J Neurochem. 2012 Oct;123(1):73-83. doi: 10.1111/j.1471-4159.2012.07876.x. Epub 2012 Aug 16. PubMed PMID: 22804734.
7: Thomsen MS, El-Sayed M, Mikkelsen JD. Differential immediate and sustained memory enhancing effects of alpha7 nicotinic receptor agonists and allosteric modulators in rats. PLoS One. 2011;6(11):e27014. doi: 10.1371/journal.pone.0027014. Epub 2011 Nov 9. PubMed PMID: 22096516; PubMed Central PMCID: PMC3212529.
