Pharmacological Profile of 2-Bromoterguride at Human Dopamine D2, Porcine Serotonin 5-Hydroxytryptamine 2A, and α2C-Adrenergic Receptors, and Its Antipsychotic-Like Effects in Rats

Jantschak, Florian; Brosda, Jan; Franke, Robert T.; Fink, Heidrun; Möller, Dorothée; Hübner, Harald; Gmeiner, Peter; Pertz, Heinz H.

doi:10.1124/jpet.113.205997

Cited by 9 publications

(18 citation statements)

References 52 publications

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“…This consideration is also relevant for both aripiprazole and FAUC350, which have been shown to exhibit biased signaling properties at D2R with respect to the activation of G protein- or β-arrestin-pathways, to Gα i /Gα o -signaling, or the stimulation of ERK1/2 phosphorylation [25], [59], [60]. Therefore, future studies will be required, ideally based on atomistic templates, to sample the conformations of a certain receptor-effector-complex entirely in order to explore the molecular determinants of biased agonism.…”

Section: Discussionmentioning

confidence: 99%

Active-State Model of a Dopamine D2 Receptor - Gαi Complex Stabilized by Aripiprazole-Type Partial Agonists

et al. 2014

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Partial agonists exhibit a submaximal capacity to enhance the coupling of one receptor to an intracellular binding partner. Although a multitude of studies have reported different ligand-specific conformations for a given receptor, little is known about the mechanism by which different receptor conformations are connected to the capacity to activate the coupling to G-proteins. We have now performed molecular-dynamics simulations employing our recently described active-state homology model of the dopamine D2 receptor-Gαi protein-complex coupled to the partial agonists aripiprazole and FAUC350, in order to understand the structural determinants of partial agonism better. We have compared our findings with our model of the D2R-Gαi-complex in the presence of the full agonist dopamine. The two partial agonists are capable of inducing different conformations of important structural motifs, including the extracellular loop regions, the binding pocket and, in particular, intracellular G-protein-binding domains. As G-protein-coupling to certain intracellular epitopes of the receptor is considered the key step of allosterically triggered nucleotide-exchange, it is tempting to assume that impaired coupling between the receptor and the G-protein caused by distinct ligand-specific conformations is a major determinant of partial agonist efficacy.

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Section: Discussionmentioning

confidence: 99%

Active-State Model of a Dopamine D2 Receptor - Gαi Complex Stabilized by Aripiprazole-Type Partial Agonists

et al. 2014

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“…Talipexole is an azepine derivative classified as a D2R agonist agent. Some early studies suggested a partial agonist activity of this compound because of its ability to inhibit the γ-butyrolactone-induced increase in dopamine striatal synthesis without inducing hyperactivity in mice, thus indicating full agonist properties at presynaptic D2Rs [ 170 ]. However, when clinically tested for the treatment of schizophrenia, only a scarce but significant reduction in negative symptoms score was found, without effects on positive symptoms [ 171 ].…”

Section: New Partial Agonists For Potential Use In Schizophreniamentioning

confidence: 99%

Update on the Mechanism of Action of Aripiprazole: Translational Insights into Antipsychotic Strategies Beyond Dopamine Receptor Antagonism

Bartolomeis¹,

Tomasetti²,

Iasevoli³

2015

CNS Drugs

135

109

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Dopamine partial agonism and functional selectivity have been innovative strategies in the pharmacological treatment of schizophrenia and mood disorders and have shifted the concept of dopamine modulation beyond the established approach of dopamine D2 receptor (D2R) antagonism. Despite the fact that aripiprazole was introduced in therapy more than 12 years ago, many questions are still unresolved regarding the complexity of the effects of this agent on signal transduction and intracellular pathways, in part linked to its pleiotropic receptor profile. The complexity of the mechanism of action has progressively shifted the conceptualization of this agent from partial agonism to functional selectivity. From the induction of early genes to modulation of scaffolding proteins and activation of transcription factors, aripiprazole has been shown to affect multiple cellular pathways and several cortical and subcortical neurotransmitter circuitries. Growing evidence shows that, beyond the consequences of D2R occupancy, aripiprazole has a unique neurobiology among available antipsychotics. The effect of chronic administration of aripiprazole on D2R affinity state and number has been especially highlighted, with relevant translational implications for long-term treatment of psychosis. The hypothesized effects of aripiprazole on cell-protective mechanisms and neurite growth, as well as the differential effects on intracellular pathways [i.e. extracellular signal-regulated kinase (ERK)] compared with full D2R antagonists, suggest further exploration of these targets by novel and future biased ligand compounds. This review aims to recapitulate the main neurobiological effects of aripiprazole and discuss the potential implications for upcoming improvements in schizophrenia therapy based on dopamine modulation beyond D2R antagonism.

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Section: Introductionmentioning

confidence: 99%

“…We recently showed that 2-bromoterguride, an ergot derivative, mechanistically mimicked aripiprazole as a D 2 receptor partial agonist (Jantschak et al 2013 ). However, compared with aripiprazole, 2-bromoterguride exhibited much higher affinity for 5-HT 2A receptors and α 2C -adrenoceptors and much lower affinity for histamine H 1 receptors (Jantschak et al 2013 ). Preclinical tests using rats confirmed that the multifunctional drug 2-bromoterguride had antidopaminergic activity as demonstrated by the inhibition of amphetamine-induced locomotion (AIL) and exhibited low EPS liability as shown by the failure to produce catalepsy.…”

Section: Introductionmentioning

confidence: 99%

2-Bromoterguride–a potential atypical antipsychotic drug without metabolic effects in rats

et al. 2016

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RationaleRecently, we showed that 2-bromoterguride acted as a dopamine D2 receptor partial agonist, a serotonin 5-HT2A and α2C-adrenergic receptor antagonist, and exhibited antidopaminergic efficacy in amphetamine-induced locomotion (AIL) in rats without inducing catalepsy.ObjectiveTo extend our knowledge on the antipsychotic effects of 2-bromoterguride, we used convergent preclinical animal models and tests; i.e., conditioned avoidance response (CAR), predictive of antipsychotic-like effects; Fos protein expression, a molecular marker for (atypical) antipsychotic activity; wet dog shake behavior, a test for the in vivo effects of drugs acting on central 5-HT2A receptors; and investigated metabolic changes as a common side effect of atypical antipsychotic drugs (APDs).ResultsAcute treatment with 2-bromoterguride (0.1 and 0.3 mg/kg) decreased the CAR at 30, 90, and 270 min post-injection in rats without inducing escape failures at any time. Fos protein expression, as shown by Western blotting, was enhanced by 2-bromoterguride in the nucleus accumbens (NAc), the dorsolateral striatum (dStr), and the medial prefrontal cortex (mPFC). (±)-2,5-Dimethoxy-4-iodoamphetamine (DOI)-induced wet dog shakes in rats were reduced by 2-bromoterguride. Chronic treatment with 2-bromoterguride did not affect metabolic parameters such as body weight development and body fat composition as well as behavioral parameters such as food intake and locomotor activity.ConclusionsOur data suggest that 2-bromoterguride is a promising candidate in the treatment of schizophrenia due to its atypical antipsychotic-like activity and its inability to induce weight gain.

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Pharmacological Profile of 2-Bromoterguride at Human Dopamine D₂, Porcine Serotonin 5-Hydroxytryptamine 2A, and α_2C-Adrenergic Receptors, and Its Antipsychotic-Like Effects in Rats

Cited by 9 publications

References 52 publications

Active-State Model of a Dopamine D2 Receptor - Gαi Complex Stabilized by Aripiprazole-Type Partial Agonists

Active-State Model of a Dopamine D2 Receptor - Gαi Complex Stabilized by Aripiprazole-Type Partial Agonists

Update on the Mechanism of Action of Aripiprazole: Translational Insights into Antipsychotic Strategies Beyond Dopamine Receptor Antagonism

2-Bromoterguride–a potential atypical antipsychotic drug without metabolic effects in rats

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