SL651498
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| Formula | C23H20FN3O2 |
| Molar mass | 389.430 g·mol−1 |
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SL651498 is an anxiolytic and anticonvulsant drug used in scientific research, with a chemical structure most closely related to β-carboline derivatives such as abecarnil and gedocarnil.[1] It has similar effects to benzodiazepine drugs, but is structurally distinct and so is classed as a nonbenzodiazepine anxiolytic.
SL651498 is a subtype-selective GABAA agonist, which acts as a full agonist at α2 and α3 subtypes, and as a partial agonist at α1 and α5 (although its action at α5 subtypes is much weaker than at the others). In animal studies, it has primarily anxiolytic effects, although some sedation, ataxia and muscle relaxant effects are observed at higher doses.[2] It substitutes fully for the anxiolytic benzodiazepine chlordiazepoxide, but only partially substituted for the imidazopyridine hypnotic drug zolpidem and the benzodiazepine hypnotic triazolam.[3][4] When given repeatedly it failed to produce tolerance or dependence, probably due to its low affinity and efficacy at the α5 subtype.[5]
SL651498 has been suggested for development as a novel non-sedating anxiolytic drug for humans, although it is still only at an early stage of research.[6] Preliminary human trials suggest similar efficacy to lorazepam as an anxiolytic, but with little or no sedation or impairment of memory, motor skills or cognitive function.[7]
There are other possibly anxioselective compounds in development, such as L-838,417, NGD 91-3.[8]
References
[edit]- ^ Sevrin M, Maloizel C, Evanno Y, Legalloudec O, George P. (Sanofi-Synthelabo). 1H-Pyrido[3,4-b]indole-4-carboxamide derivatives, preparation and application thereof in therapeutics. US Patent 6075021
- ^ Griebel G, Perrault G, Simiand J, Cohen C, Granger P, Depoortere H, et al. (2003). "SL651498, a GABAA receptor agonist with subtype-selective efficacy, as a potential treatment for generalized anxiety disorder and muscle spasms". CNS Drug Reviews. 9 (1): 3–20. doi:10.1111/j.1527-3458.2003.tb00241.x. PMC 6741675. PMID 12595909.
- ^ Griebel G, Perrault G, Simiand J, Cohen C, Granger P, Decobert M, et al. (August 2001). "SL651498: an anxioselective compound with functional selectivity for alpha2- and alpha3-containing gamma-aminobutyric acid(A) (GABA(A)) receptors". The Journal of Pharmacology and Experimental Therapeutics. 298 (2): 753–68. PMID 11454940.
- ^ Licata SC, Platt DM, Cook JM, Sarma PV, Griebel G, Rowlett JK (June 2005). "Contribution of GABAA receptor subtypes to the anxiolytic-like, motor, and discriminative stimulus effects of benzodiazepines: studies with the functionally selective ligand SL651498 [6-fluoro-9-methyl-2-phenyl-4-(pyrrolidin-1-yl-carbonyl)-2,9-dihydro-1H-pyridol[3,4-b]indol-1-one]". The Journal of Pharmacology and Experimental Therapeutics. 313 (3): 1118–25. doi:10.1124/jpet.104.081612. PMID 15687371. S2CID 5683444.
- ^ Mirza NR, Nielsen EØ (March 2006). "Do subtype-selective gamma-aminobutyric acid A receptor modulators have a reduced propensity to induce physical dependence in mice?". The Journal of Pharmacology and Experimental Therapeutics. 316 (3): 1378–85. doi:10.1124/jpet.105.094474. PMID 16352707. S2CID 22700422.
- ^ Whiting PJ (February 2006). "GABA-A receptors: a viable target for novel anxiolytics?". Current Opinion in Pharmacology. 6 (1): 24–9. doi:10.1016/j.coph.2005.08.005. PMID 16359919.
- ^ de Haas SL, Franson KL, Schmitt JA, Cohen AF, Fau JB, Dubruc C, van Gerven JM (August 2009). "The pharmacokinetic and pharmacodynamic effects of SL65.1498, a GABA-A alpha2,3 selective agonist, in comparison with lorazepam in healthy volunteers". Journal of Psychopharmacology. 23 (6): 625–32. doi:10.1177/0269881108092595. PMID 18635696. S2CID 24874089.
- ^ Atack JR (August 2003). "Anxioselective compounds acting at the GABA(A) receptor benzodiazepine binding site". Current Drug Targets. CNS and Neurological Disorders. 2 (4): 213–32. doi:10.2174/1568007033482841. PMID 12871032.