| Class: | Dopamine D3 receptor antagonist |
| Cas Number: | 863680-46-0 |
| Pubchem: | 11784937 |
| Chemspiderid: | 32701679 |
| Unii: | Y5OZ63HC3V |
| Chembl: | 3590085 |
| Synonyms: | GSK598809 |
| Iupac Name: | 5-[5-[3-[(1''S'',5''R'')-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 |
| C: | 22 |
| H: | 23 |
| F: | 4 |
| N: | 5 |
| O: | 1 |
| S: | 1 |
| Smiles: | 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 |
| Stdinchi: | 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 |
| Stdinchikey: | 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]
The drug is highly selective for the dopamine D3 receptor (Ki = 6.2nM) over the dopamine D2 receptor (Ki = 740nM) (~120-fold preference for the D3 receptor over the D2 receptor). A single dose of GSK-598809 achieved 72 to 89% occupancy of the D3 receptor in smokers.
Side effects of GSK-598809 in clinical trials have included headache and somnolence with no sedation or extrapyramidal symptoms. This is in contrast to dopamine D2 receptor antagonists, which are associated with sedation, motor side effects, reduced activity, and emotional blunting. However, GSK-598809 has been associated with cardiovascular side effects at high doses. 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. 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.
GSK-598809 was first described in the scientific literature by 2009.[4] [5] 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. GSK-598809 reached at least phase 1 clinical trials. 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.[6] In any case, signs of clinical efficacy were reported to have been observed.