“SL651498”的意思、由来-开放百科全书

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 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.^[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

1. ^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
2. ^{{cite journal | pmid = 12595909| year = 2003| last1 = Griebel| first1 = G.| 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| last2 = Perrault| first2 = G.| last3 = Simiand| first3 = J.| last4 = Cohen| first4 = C.| last5 = Granger| first5 = P.| last6 = Depoortere| first6 = H.| last7 = Françon| first7 = D.| last8 = Avenet| first8 = P.| last9 = Schoemaker| first9 = H.| last10 = Evanno| first10 = Y.| last11 = Sevrin| first11 = M.| last12 = George| first12 = P.| last13 = Scatton| first13 = B.}}
3. ^{{cite journal | pmid = 11454940| year = 2001| last1 = Griebel| first1 = G.| 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| last2 = Perrault| first2 = G.| last3 = Simiand| first3 = J.| last4 = Cohen| first4 = C.| last5 = Granger| first5 = P.| last6 = Decobert| first6 = M.| last7 = Françon| first7 = D.| last8 = Avenet| first8 = P.| last9 = Depoortere| first9 = H.| last10 = Tan| first10 = S.| last11 = Oblin| first11 = A.| last12 = Schoemaker| first12 = H.| last13 = Evanno| first13 = Y.| last14 = Sevrin| first14 = M.| last15 = George| first15 = P.| last16 = Scatton| first16 = B.}}
4. ^{{cite journal | pmid = 15687371 | year = 2005 | last1 = Licata | first1 = S. C. | 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-pyridol3,4-bindol-1-one | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 313 | issue = 3 | pages = 1118–25 | last2 = Platt | first2 = D. M. | last3 = Cook | first3 = J. M. | last4 = Sarma | first4 = P. V. | last5 = Griebel | first5 = G. | last6 = Rowlett | first6 = J. K. | doi = 10.1124/jpet.104.081612 }}
5. ^{{cite journal | pmid = 16352707 | year = 2006 | last1 = Mirza | first1 = N. R. | 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 | doi = 10.1124/jpet.105.094474 }}
6. ^{{cite journal | pmid = 16359919| year = 2006| last1 = Whiting| first1 = P. J.| title = GABA-A receptors: A viable target for novel anxiolytics?| journal = Current Opinion in Pharmacology| volume = 6| issue = 1| pages = 24–9| doi = 10.1016/j.coph.2005.08.005}}
7. ^{{cite journal | pmid = 18635696 | year = 2009 | last1 = De Haas | first1 = S. L. | 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 (Oxford, England) | volume = 23 | issue = 6 | pages = 625–32 | last2 = Franson | first2 = K. L. | last3 = Schmitt | first3 = J. A. | last4 = Cohen | first4 = A. F. | last5 = Fau | first5 = J. B. | last6 = Dubruc | first6 = C. | last7 = Van Gerven | first7 = J. M. | doi = 10.1177/0269881108092595 }}
8. ^{{cite journal | doi=10.2174/1568007033482841 | title=Anxioselective Compounds Acting at the GABAA Receptor Benzodiazepine Binding Site | journal=Current Drug Target -Cns & Neurological Disorders | volume=2 | issue=4 | pages=213–232 | year=2003 | last1=Atack | first1=John }}