GSK-598809 is a selective

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

D₃ receptor

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.substance-related disorder Substance-related disorders is a class of mental disorders that affect a person's brain and behavior, leading to their inability to control their use of substances like drugs, alcohol, or medications. The disorders can lead to large societal probl ...

s, smoking withdrawal, and

eating disorder An eating disorder is a mental disorder defined by abnormal eating behaviors that adversely affect a person's health, physical or mental health, mental health. These behaviors may include eating too much food or too little food. Types of eatin ...

s like

binge eating disorder Binge eating disorder (BED) is an eating disorder characterized by frequent and recurrent binge eating episodes with associated negative psychological and social problems, but without the compensatory behaviors common to bulimia nervosa, OSFE ...

. The drug is highly selective for the dopamine D₃ receptor (K_i = 6.2nM) over the dopamine D₂ receptor (K_i = 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 effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s of GSK-598809 in

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

s have included

headache A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...

and

somnolence Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling aslee ...

with no

sedation Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure. Examples of drugs which can be used for sedation include isoflurane, diethyl ether, ...

extrapyramidal symptoms Extrapyramidal symptoms (EPS) are signs and symptoms, symptoms that are wikt:archetypical, archetypically associated with the extrapyramidal system of the brain's cerebral cortex. When such symptoms are caused by medications or other drugs, they ...

. 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 In vertebrates, the circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the body. It includes the cardiovascular system, or vascular system, that consists of the heart a ...

side effects at high doses. It increases

blood pressure Blood pressure (BP) is the pressure of Circulatory system, circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term ...

in animals and this effect was especially strong in the presence of

cocaine Cocaine is a tropane alkaloid and central nervous system stimulant, derived primarily from the leaves of two South American coca plants, ''Erythroxylum coca'' and ''Erythroxylum novogranatense, E. novogranatense'', which are cultivated a ...

, which dampened enthusiasm for its clinical development for

cocaine use disorder Cocaine dependence is a neurological disorder that is characterized by withdrawal symptoms upon cessation from cocaine use. It also often coincides with cocaine addiction which is a biopsychosocial disorder characterized by persistent use of coc ...

. 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 Scientific literature encompasses a vast body of academic papers that spans various disciplines within the natural and social sciences. It primarily consists of academic papers that present original empirical research and theoretical ...

by 2009. 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. In any case, signs of clinical efficacy were reported to have been observed.

References

{{Dopamine receptor modulators D3 antagonists Experimental drugs Oxazoles Thioethers Triazoles Trifluoromethyl compounds

See also

References