Chemistry:GSK-598809
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
- ↑ 1.0 1.1 1.2 "GSK 598809". 1 August 2023. https://adisinsight.springer.com/drugs/800025964.
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 "Pharmacological targeting of dopamine D3 receptors: Possible clinical applications of selective drugs". Eur Neuropsychopharmacol 25 (9): 1437–1447. September 2015. doi:10.1016/j.euroneuro.2015.07.012. PMID 26298833.
- ↑ 3.0 3.1 3.2 3.3 3.4 3.5 "Current Perspectives on Selective Dopamine D3 Receptor Antagonists/Partial Agonists as Pharmacotherapeutics for Opioid and Psychostimulant Use Disorders". Therapeutic Applications of Dopamine D3 Receptor Function. Current Topics in Behavioral Neurosciences. 60. 2023. pp. 157–201. doi:10.1007/7854_2022_347. ISBN 978-3-031-23057-8.
- ↑ 4.0 4.1 4.2 "Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders". Biomolecules 11 (1): 104. January 2021. doi:10.3390/biom11010104. PMID 33466844.
- ↑ "Emerging therapeutic targets for the treatment of nicotine addiction". Expert Rev Clin Pharmacol 2 (3): 221–225. May 2009. doi:10.1586/ecp.09.6. PMID 24410700.
- ↑ "Mechanism-based medication development for the treatment of nicotine dependence". Acta Pharmacol Sin 30 (6): 723–739. June 2009. doi:10.1038/aps.2009.46. PMID 19434058.
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