SL651498

{{Short description|Chemical compound}}

{{Drugbox

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| verifiedrevid = 464385430

| IUPAC_name = 6-Fluoro-9-methyl-2-phenyl-4-(pyrrolidin-1-yl-carbonyl)-2,9-dihydro-1H-pyrido[3,4-b]indol-1-one

| image = SL-651,498.svg

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| CAS_number_Ref = {{cascite|changed|??}}

| CAS_number = 205881-86-3

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| UNII = 082VH54RF1

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| ChemSpiderID = 8084030

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 1S/C23H20FN3O2/c1-25-19-10-9-15(24)13-17(19)20-18(22(28)26-11-5-6-12-26)14-27(23(29)21(20)25)16-7-3-2-4-8-16/h2-4,7-10,13-14H,5-6,11-12H2,1H3

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = QQWHWWDIFGNCLV-UHFFFAOYSA-N

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| C=23 | H=20 | F=1 | N=3 | O=2

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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.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. [https://patents.google.com/patent/US6075021 US Patent 6075021] It has similar effects to benzodiazepine drugs, but is structurally distinct and so is classed as a nonbenzodiazepine anxiolytic.

SL651498 is a subtype-selective GABA_A 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.{{cite journal | vauthors = Griebel G, Perrault G, Simiand J, Cohen C, Granger P, Depoortere H, Françon D, Avenet P, Schoemaker H, Evanno Y, Sevrin M, George P, Scatton B | display-authors = 6 | title = SL651498, a GABAA receptor agonist with subtype-selective efficacy, as a potential treatment for generalized anxiety disorder and muscle spasms | journal = CNS Drug Reviews | volume = 9 | issue = 1 | pages = 3–20 | year = 2003 | pmid = 12595909 | pmc = 6741675 | doi = 10.1111/j.1527-3458.2003.tb00241.x }} It substitutes fully for the anxiolytic benzodiazepine chlordiazepoxide, but only partially substituted for the imidazopyridine hypnotic drug zolpidem and the benzodiazepine hypnotic triazolam.{{cite journal | vauthors = Griebel G, Perrault G, Simiand J, Cohen C, Granger P, Decobert M, Françon D, Avenet P, Depoortere H, Tan S, Oblin A, Schoemaker H, Evanno Y, Sevrin M, George P, Scatton B | display-authors = 6 | title = SL651498: an anxioselective compound with functional selectivity for alpha2- and alpha3-containing gamma-aminobutyric acid(A) (GABA(A)) receptors | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 298 | issue = 2 | pages = 753–68 | date = August 2001 | pmid = 11454940 }}{{cite journal | vauthors = Licata SC, Platt DM, Cook JM, Sarma PV, Griebel G, Rowlett JK | s2cid = 5683444 | title = 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] | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 313 | issue = 3 | pages = 1118–25 | date = June 2005 | pmid = 15687371 | doi = 10.1124/jpet.104.081612 }} When given repeatedly it failed to produce tolerance or dependence, probably due to its low affinity and efficacy at the α₅ subtype.{{cite journal | vauthors = Mirza NR, Nielsen EØ | s2cid = 22700422 | title = Do subtype-selective gamma-aminobutyric acid A receptor modulators have a reduced propensity to induce physical dependence in mice? | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 316 | issue = 3 | pages = 1378–85 | date = March 2006 | pmid = 16352707 | doi = 10.1124/jpet.105.094474 }}

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.{{cite journal | vauthors = Whiting PJ | title = GABA-A receptors: a viable target for novel anxiolytics? | journal = Current Opinion in Pharmacology | volume = 6 | issue = 1 | pages = 24–9 | date = February 2006 | pmid = 16359919 | doi = 10.1016/j.coph.2005.08.005 }} 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.{{cite journal | vauthors = de Haas SL, Franson KL, Schmitt JA, Cohen AF, Fau JB, Dubruc C, van Gerven JM | s2cid = 24874089 | title = The pharmacokinetic and pharmacodynamic effects of SL65.1498, a GABA-A alpha2,3 selective agonist, in comparison with lorazepam in healthy volunteers | journal = Journal of Psychopharmacology | volume = 23 | issue = 6 | pages = 625–32 | date = August 2009 | pmid = 18635696 | doi = 10.1177/0269881108092595 }}

There are other possibly anxioselective compounds in development, such as L-838,417, NGD 91-3.{{cite journal | vauthors = Atack JR | title = Anxioselective compounds acting at the GABA(A) receptor benzodiazepine binding site | journal = Current Drug Targets. CNS and Neurological Disorders | volume = 2 | issue = 4 | pages = 213–32 | date = August 2003 | pmid = 12871032 | doi = 10.2174/1568007033482841 }}