SH-053-R-CH3-2′F

SH-053-R-CH3-2′F is a drug used in scientific research which is a benzodiazepine derivative. It produces some of the same effects as other benzodiazepines, but is much more subtype-selective than most other drugs of this class, having high selectivity, binding affinity and efficacy at the α₅ subtype of the GABA_A receptor. This gives much tighter control of the effects produced, and so while SH-053-R-CH3-2′F retains sedative and anxiolytic effects, it does not cause ataxia at moderate doses.[1] SH-053-R-CH3-2′F also blocks the nootropic effects of the α₅-selective inverse agonist PWZ-029, so amnesia is also a likely side effect.[2]

SH-053-R-CH3-2′F

Identifiers
IUPAC name (R)-8-ethynyl-6-(2-fluorophenyl)-4-methyl-4H-2,5,10b-triaza-benzo[e]azulene-3-carboxylic acid ethyl ester
CAS Number	872874-14-1
PubChem CID	11574585
ChemSpider	9749355
Chemical and physical data
Formula	C23H18FN3O2
Molar mass	387.414 g·mol^−1
3D model (JSmol)	Interactive image
SMILES Fc2ccccc2C1=NC(C)c3c(C(=O)OCC)ncn3-c(cc4)c1cc4C#C
InChI InChI=1S/C23H18FN3O2/c1-4-15-10-11-19-17(12-15)20(16-8-6-7-9-18(16)24)26-14(3)22-21(23(28)29-5-2)25-13-27(19)22/h1,6-14H,5H2,2-3H3/t14-/m1/s1 Key:NGYKELBMVXBFSM-CQSZACIVSA-N

Replacement of the ester function by an amide, realized in analogs such as MP-III-022 and GL-II-73, improves selectivity, efficacy and kinetic behavior.[3][4][5]

See also

• QH-ii-066
• SH-I-048A

References

1. Savić MM, Huang S, Furtmüller R, Clayton T, Huck S, Obradović DI, Ugresić ND, Sieghart W, Bokonjić DR, Cook JM (Jan 2008). "Are GABAA receptors containing alpha5 subunits contributing to the sedative properties of benzodiazepine site agonists?". Neuropsychopharmacology. 33 (2): 332–9. doi:10.1038/sj.npp.1301403. PMID 17392731.
2. Savić MM, Clayton T, Furtmüller R, Gavrilović I, Samardzić J, Savić S, Huck S, Sieghart W, Cook JM (May 2008). "PWZ-029, a compound with moderate inverse agonist functional selectivity at GABA(A) receptors containing alpha5 subunits, improves passive, but not active, avoidance learning in rats". Brain Research. 1208: 150–9. doi:10.1016/j.brainres.2008.02.020. PMC 2577822. PMID 18394590.
3. Stamenić TT, Poe MM, Rehman S, Santrač A, Divović B, Scholze P, Ernst M, Cook JM, Savić MM (2016). "Ester to amide substitution improves selectivity, efficacy and kinetic behavior of a benzodiazepine positive modulator of GABAA receptors containing the α5 subunit". Eur. J. Pharmacol. 791: 433–443. doi:10.1016/j.ejphar.2016.09.016. PMC 5107132. PMID 27639297.
4. Cook JM, Li G, Poe M, Savic M, Sibille E. Treatment of cognitive and mood symptoms in neurodegenerative and neuropsychiatric disorders with alpha5-containing gabaa receptor agonists. Patent application CA3016491
5. Prevot TD, et al. Novel Benzodiazepine-Like Ligands with Various Anxiolytic, Antidepressant, or Pro-Cognitive Profiles. Molecular Neuropsychiatry, 2019; 1. doi:10.1159/000496086