GSK-598809

GSK-598809
Clinical data
Other namesGSK598809
Drug classDopamine D3 receptor antagonist
Identifiers
  • 5-[5-[3-[(1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexan-3-yl]propylsulfanyl]-4-methyl-1,2,4-triazol-3-yl]-4-methyl-1,3-oxazole
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC22H23F4N5OS
Molar mass481.51 g·mol−1
3D model (JSmol)
  • CC1=C(OC=N1)C2=NN=C(N2C)SCCCN3C[C@@H]4C[C@@]4(C3)C5=C(C=C(C=C5)C(F)(F)F)F
  • InChI=1S/C22H23F4N5OS/c1-13-18(32-12-27-13)19-28-29-20(30(19)2)33-7-3-6-31-10-15-9-21(15,11-31)16-5-4-14(8-17(16)23)22(24,25)26/h4-5,8,12,15H,3,6-7,9-11H2,1-2H3/t15-,21-/m0/s1
  • Key:ZKRWPAYTJMRKLJ-BTYIYWSLSA-N

GSK-598809 is a selective dopamine D3 receptor antagonist that is or was under development for the treatment of substance-related disorders, smoking withdrawal, and eating disorders like binge eating disorder.[1][2][3][4]

The drug is highly selective for the dopamine D3 receptor (Ki = 6.2 nM) over the dopamine D2 receptor (Ki = 740 nM) (~120-fold preference for the D3 receptor over the D2 receptor).[3] A single dose of GSK-598809 achieved 72 to 89% occupancy of the D3 receptor in smokers.[3]

Side effects of GSK-598809 in clinical trials have included headache and somnolence with no sedation or extrapyramidal symptoms.[2] This is in contrast to dopamine D2 receptor antagonists, which are associated with sedation, motor side effects, reduced activity, and emotional blunting.[2] However, GSK-598809 has been associated with cardiovascular side effects at high doses.[2] It increases blood pressure in animals and this effect was especially strong in the presence of cocaine, which dampened enthusiasm for its clinical development for cocaine use disorder.[3] However, other more recently developed and selective D3 receptor antagonists like (R)-VK4-116 and (R)-VK4-40 do not share these cardiovascular side effects.[3]

GSK-598809 was first described in the scientific literature by 2009.[5][6] As of August 2023, no recent development of GSK-598809 has been reported for substance-related disorders, smoking withdrawal, or eating disorders since July 2016.[1] GSK-598809 reached at least phase 1 clinical trials.[1][2] According to a 2021 review, the clinical effects of GSK-598809 and other experimental dopamine D3 receptor antagonists were mixed or unsatisfactory and thus their development was discontinued early into clinical trials.[4] In any case, signs of clinical efficacy were reported to have been observed.[3][2][4]

See also

References

  1. ^ a b c "GSK 598809". AdisInsight. 1 August 2023. Retrieved 25 September 2024.
  2. ^ a b c d e f Pich EM, Collo G (September 2015). "Pharmacological targeting of dopamine D3 receptors: Possible clinical applications of selective drugs". Eur Neuropsychopharmacol. 25 (9): 1437–1447. doi:10.1016/j.euroneuro.2015.07.012. PMID 26298833.
  3. ^ a b c d e f Newman AH, Xi ZX, Heidbreder C (2023). "Current Perspectives on Selective Dopamine D3 Receptor Antagonists/Partial Agonists as Pharmacotherapeutics for Opioid and Psychostimulant Use Disorders". Curr Top Behav Neurosci. Current Topics in Behavioral Neurosciences. 60: 157–201. doi:10.1007/7854_2022_347. ISBN 978-3-031-23057-8. PMC 9652482. PMID 35543868.
  4. ^ a b c Kiss B, Laszlovszky I, Krámos B, Visegrády A, Bobok A, Lévay G, Lendvai B, Román V (January 2021). "Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders". Biomolecules. 11 (1): 104. doi:10.3390/biom11010104. PMC 7830622. PMID 33466844.
  5. ^ Kenny PJ (May 2009). "Emerging therapeutic targets for the treatment of nicotine addiction". Expert Rev Clin Pharmacol. 2 (3): 221–225. doi:10.1586/ecp.09.6. PMID 24410700.
  6. ^ Xi ZX, Spiller K, Gardner EL (June 2009). "Mechanism-based medication development for the treatment of nicotine dependence". Acta Pharmacol Sin. 30 (6): 723–739. doi:10.1038/aps.2009.46. PMC 3713229. PMID 19434058.

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