Dopamine D₃Receptor Antagonist (GSK598809) Potentiates the Hypertensive Effects of Cocaine in Conscious, Freely-Moving Dogs

Abstract

The chronic and relapsing nature of addiction presents unique challenges for ensuring the safety of a potential medication. A patient may use cocaine, for example, while taking the medication or take more medication than prescribed. Thus, a potential medication must be safe and not exacerbate the effects of other substance use disorders. The US Food and Drug Administration has established guidelines recommending safety studies to investigate potential undesirable pharmacodynamic effects of a substance in relation to exposure in the therapeutic range and above. Hence, we assessed the interaction between this selective dopamine D 3 receptor antagonist and cocaine on hemodynamics and cardiac function in freely-moving, telemetered dogs before conducting a clinical trial. GSK598809 increased the hemodynamic effect of cocaine in this model. Thus, the increase in blood pressure after intravenous cocaine was greater in animals that had been pretreated with GSK598809 compared with vehicle. This finding suggests that GSK598809 in particular, and perhaps dopamine D 3 receptor antagonists as a class, may produce unacceptable cardiovascular risks as medications to treat cocaine use disorder.

Dopamine D3R antagonist VK4-116 attenuates oxycodone self-administration and reinstatement without compromising its antinociceptive effects

“…Despite the involvement of D3R in drug addiction, the clinical translation remains challenging due to either the lack of appropriate absorption, distribution, metabolism, and excretion (ADME) properties or predicted cardiotoxicity of previously reported D3R antagonists in the presence of cocaine [26,27]. As a result of these limitations, efforts to develop a new generation of D3R agents that are devoid of these undesirable attributes have resulted in the discovery of the highly selective D3R antagonist, VK4-116 (D3R K i = 6.8 nM; D2R K i = 11,400 nM [28]).…”

Highly Selective Dopamine D3 Receptor (D3R) Antagonists and Partial Agonists Based on Eticlopride and the D3R Crystal Structure: New Leads for Opioid Dependence Treatment

“…1) caused significant hypertension in dogs in the presence of cocaine, may preclude further development of these agents toward cocaine addiction. 8 Nevertheless, efficacy in both animal models of other substance use disorders, including heroin, alcohol and nicotine support continued efforts toward developing D 3 R-selective antagonists and/or partial agonists that are metabolically stable and have appropriate drug-like properties for potential translation to specific drug abusing populations. 1,9,10 …”

“…14,18,19 In addition, the preponderance of published studies have focused on developing these target molecules toward cocaine addiction, and yet, a recent report suggests that toxic hypertension may result from treatment with a D 3 R antagonist in the presence of cocaine (i.e., if the patient relapsed to cocaine taking), further dampening enthusiasm for developing these molecules for human psychostimulant abusers. 8 …”

Design, synthesis, and evaluation of bitopic arylpiperazine-phthalimides as selective dopamine D3 receptor agonists

“…Although GSK598809, a D 3 R antagonist, exhibited high D 3 R selectivity compared to D 2 R, it induced significant hypertension in dogs in the presence of cocaine. 12 Compounds 1 and 2 displayed subnanomolar affinity for D 3 R and striking selectivity (4682-fold and 55 556-fold, respectively, Fig. 1).…”

“…Although extensive efforts have been made by medicinal chemists and a number of promising D 3 R-selective ligands have been developed, few truly selective or biased ligands have been approved by the Food and Drug Administration (FDA) or have progressed to clinical trials. [10][11][12][13][14][15] Compound BP897 has been shown to display subnanomolar affinity for D 3 R as well as moderate selectivity (Fig. 1).…”