ANA-12

ANA-12
Clinical data
ATC code	None;
Identifiers
	IUPAC name N-[2-[(2-oxoazepan-3-yl)carbamoyl]phenyl]-1-benzothiophene-2-carboxamide;
CAS Number	219766-25-3 ;
PubChem CID	2799722;
ChemSpider	2078460;
UNII	54S4JPT8JX;
CompTox Dashboard (EPA)	DTXSID501045818 ;
ECHA InfoCard	100.229.925
Chemical and physical data
Formula	C22H21N3O3S
Molar mass	407.49 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES C1CCNC(=O)C(C1)NC(=O)C2=CC=CC=C2NC(=O)C3=CC4=CC=CC=C4S3;
	InChI InChI=1S/C22H21N3O3S/c26-20(25-17-10-5-6-12-23-21(17)27)15-8-2-3-9-16(15)24-22(28)19-13-14-7-1-4-11-18(14)29-19/h1-4,7-9,11,13,17H,5-6,10,12H2,(H,23,27)(H,24,28)(H,25,26); Key:TUSCYCAIGRVBMD-UHFFFAOYSA-N;

ANA-12 is a selective, small-molecule non-competitive antagonist of TrkB, the main receptor of brain-derived neurotrophic factor (BDNF).^[1] ANA-12 was originally discovered and developed by Cazorla M. and colleagues at Université Paris and Inserm in 2011.^[1] The compound crosses the blood-brain-barrier and exerts central TrkB blockade, producing effects as early as 30 minutes (~400 nM) and as long as 6 hours (~10 nM) following intraperitoneal injection in mice.^[1] It blocks the neurotrophic actions of BDNF without compromising neuron survival.^[1]

Research

ANA-12 has two binding sites on TrkB, a high- and low-affinity site (K_d = 10 nM and 12 μM, respectively).

ANA-12 produces rapid antidepressant- and anxiolytic-like effects in animal models,^[1] the former of which have been elucidated to be mediated by blockade of BDNF signaling in the nucleus accumbens.^[2]^[3] It has also been found to alleviate methamphetamine-induced depression-like behavior (including anhedonia), behavioral sensitization, and nucleus accumbens neuroplasticity changes with subchronic (14-day) administration in mice, whereas the TrkB agonist 7,8-dihydroxyflavone was ineffective in doing so.^[4]

ANA-12 blocks the cognitive-enhancing effects of environmental enrichment and calorie restriction in rodents, which are mediated by BDNF signaling through TrkB in the hippocampus.^[5]^[6] It also blocks hippocampal neurogenesis induced by physical exercise in rodents, and may block the cognitive-enhancing effects of exercise as well.^[7]

References

^ ^a ^b ^c ^d ^e Cazorla M, Prémont J, Mann A, Girard N, Kellendonk C, Rognan D (May 2011). "Identification of a low-molecular weight TrkB antagonist with anxiolytic and antidepressant activity in mice". The Journal of Clinical Investigation. 121 (5): 1846–1857. doi:10.1172/JCI43992. PMC 3083767. PMID 21505263.
^ Zhang JC, Wu J, Fujita Y, Yao W, Ren Q, Yang C, et al. (October 2014). "Antidepressant effects of TrkB ligands on depression-like behavior and dendritic changes in mice after inflammation". The International Journal of Neuropsychopharmacology. 18 (4): pyu077. doi:10.1093/ijnp/pyu077. PMC 4360225. PMID 25628381.
^ Shirayama Y, Yang C, Zhang JC, Ren Q, Yao W, Hashimoto K (December 2015). "Alterations in brain-derived neurotrophic factor (BDNF) and its precursor proBDNF in the brain regions of a learned helplessness rat model and the antidepressant effects of a TrkB agonist and antagonist". European Neuropsychopharmacology. 25 (12): 2449–2458. doi:10.1016/j.euroneuro.2015.09.002. PMID 26419294. S2CID 851.
^ Ren Q, Ma M, Yang C, Zhang JC, Yao W, Hashimoto K (October 2015). "BDNF-TrkB signaling in the nucleus accumbens shell of mice has key role in methamphetamine withdrawal symptoms". Translational Psychiatry. 5 (10): e666. doi:10.1038/tp.2015.157. PMC 4930133. PMID 26506052.
^ Fan D, Li J, Zheng B, Hua L, Zuo Z (January 2016). "Enriched Environment Attenuates Surgery-Induced Impairment of Learning, Memory, and Neurogenesis Possibly by Preserving BDNF Expression". Molecular Neurobiology. 53 (1): 344–354. doi:10.1007/s12035-014-9013-1. PMID 25432890. S2CID 15795328.
^ Kishi T, Hirooka Y, Nagayama T, Isegawa K, Katsuki M, Takesue K, Sunagawa K (2015). "Calorie restriction improves cognitive decline via up-regulation of brain-derived neurotrophic factor: tropomyosin-related kinase B in hippocampus ofobesity-induced hypertensive rats". International Heart Journal. 56 (1): 110–115. doi:10.1536/ihj.14-168. PMID 25503654.
^ Ambrogini P, Lattanzi D, Ciuffoli S, Betti M, Fanelli M, Cuppini R (October 2013). "Physical exercise and environment exploration affect synaptogenesis in adult-generated neurons in the rat dentate gyrus: possible role of BDNF". Brain Research. 1534: 1–12. doi:10.1016/j.brainres.2013.08.023. hdl:11576/2575580. PMID 23973748. S2CID 35405574.

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[CazorlaPrémont2011-1] Cazorla M, Prémont J, Mann A, Girard N, Kellendonk C, Rognan D (May 2011). "Identification of a low-molecular weight TrkB antagonist with anxiolytic and antidepressant activity in mice". The Journal of Clinical Investigation. 121 (5): 1846–1857. doi:10.1172/JCI43992. PMC 3083767. PMID 21505263.

[pmid25628381-2] Zhang JC, Wu J, Fujita Y, Yao W, Ren Q, Yang C, et al. (October 2014). "Antidepressant effects of TrkB ligands on depression-like behavior and dendritic changes in mice after inflammation". The International Journal of Neuropsychopharmacology. 18 (4): pyu077. doi:10.1093/ijnp/pyu077. PMC 4360225. PMID 25628381.

[pmid26419294-3] Shirayama Y, Yang C, Zhang JC, Ren Q, Yao W, Hashimoto K (December 2015). "Alterations in brain-derived neurotrophic factor (BDNF) and its precursor proBDNF in the brain regions of a learned helplessness rat model and the antidepressant effects of a TrkB agonist and antagonist". European Neuropsychopharmacology. 25 (12): 2449–2458. doi:10.1016/j.euroneuro.2015.09.002. PMID 26419294. S2CID 851.

[pmid26506052-4] Ren Q, Ma M, Yang C, Zhang JC, Yao W, Hashimoto K (October 2015). "BDNF-TrkB signaling in the nucleus accumbens shell of mice has key role in methamphetamine withdrawal symptoms". Translational Psychiatry. 5 (10): e666. doi:10.1038/tp.2015.157. PMC 4930133. PMID 26506052.

[pmid25432890-5] Fan D, Li J, Zheng B, Hua L, Zuo Z (January 2016). "Enriched Environment Attenuates Surgery-Induced Impairment of Learning, Memory, and Neurogenesis Possibly by Preserving BDNF Expression". Molecular Neurobiology. 53 (1): 344–354. doi:10.1007/s12035-014-9013-1. PMID 25432890. S2CID 15795328.

[pmid25503654-6] Kishi T, Hirooka Y, Nagayama T, Isegawa K, Katsuki M, Takesue K, Sunagawa K (2015). "Calorie restriction improves cognitive decline via up-regulation of brain-derived neurotrophic factor: tropomyosin-related kinase B in hippocampus ofobesity-induced hypertensive rats". International Heart Journal. 56 (1): 110–115. doi:10.1536/ihj.14-168. PMID 25503654.

[AmbroginiLattanzi2013-7] Ambrogini P, Lattanzi D, Ciuffoli S, Betti M, Fanelli M, Cuppini R (October 2013). "Physical exercise and environment exploration affect synaptogenesis in adult-generated neurons in the rat dentate gyrus: possible role of BDNF". Brain Research. 1534: 1–12. doi:10.1016/j.brainres.2013.08.023. hdl:11576/2575580. PMID 23973748. S2CID 35405574.

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Research

See also

References