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Functionally selective G protein-coupled receptor (GPCR) ligands are valuable tools for deciphering the roles of downstream signaling pathways that potentially contribute to therapeutic effects versus side effects. Recently, we discovered both Gi/o-biased and β-arrestin2-biased D2 receptor agonists based on the FDA approved drug aripiprazole. In this work, based on another FDA approved drug, cariprazine, we conducted a structure-functional selectivity relationship (SFSR) study and discovered compound 38 (MS1768) as a potent partial agonist that selectively activates the Gi/o pathway over β-arrestin2. Unlike the dual D2R/D3R partial agonist cariprazine, compound 38 showed selective agonist activity for D2R over D3R. In fact, compound 38 exhibited potent antagonism of dopamine-stimulated β-arrestin2 recruitment. In our docking studies, compound 38 directly interacts with S1935.42 on TM5 but has no interactions with extracellular loop 2 (EL2), which appears to be in contrast to the binding poses of D2R β-arrestin2-biased ligands. In in vivo studies, compound 38 showed high D2R receptor occupancy in mice and effectively inhibited phencyclidine (PCP)-induced hyperlocomotion.
This article was published in the following journal.
Name: Journal of medicinal chemistry
G protein-coupled receptors (GPCRs) are capable of downstream signaling through distinct non-canonical pathways such as -arrestins in addition to the canonical G protein-dependent pathways. GPCR li...
Negative symptoms in schizophrenia are heterogeneous and multidimensional; effective treatments are lacking. Cariprazine, a dopamine D-preferring D/D receptor partial agonist and serotonin 5-HT recept...
Long-term remission is an important treatment goal in schizophrenia. Cariprazine, a dopamine D₃/D₂ receptor and serotonin 5-HT1A receptor partial agonist, is approved in the United States and Euro...
Agonist-induced internalization of G protein-coupled receptors (GPCRs) is a significant step in receptor kinetics and is known to be involved in receptor down-regulation. However, the dopamine D3 rece...
G protein-coupled receptors (GPCRs) are currently the target of more than 30% of the marketed medicines. However, there is an important medical need for ligands with improved pharmacological activitie...
The dopamine agonists, pramipexole (Mirapex) and ropinirole (Requip), are drugs that are used to treat symptoms of Parkinson's disease. However, these drugs can induce bothersome leg swell...
Cocaine abuse continues to represent a significant public-health concern. Cocaine likely creates its addictive effects by increasing levels of dopamine, a chemical found in the brain. GABA...
To assess the efficacy of rasagiline 1 mg as a first add-on treatment to dopamine agonist therapy in early Parkinson Disease (PD) patients, , not optimally controlled on dopamine agonists...
To study the in vivo expression of dopamine D2 receptors in prolactinoma and the predictive role of dopamine D2 receptors PET-MR imaging in the therapeutic effect of dopamine agonists.
The objective of this study is to evaluate the efficacy, safety, and tolerability of cariprazine relative to placebo for the treatment of acute exacerbation of schizophrenia.
Drugs that bind to but do not activate DOPAMINE RECEPTORS, thereby blocking the actions of dopamine or exogenous agonists. Many drugs used in the treatment of psychotic disorders (ANTIPSYCHOTIC AGENTS) are dopamine antagonists, although their therapeutic effects may be due to long-term adjustments of the brain rather than to the acute effects of blocking dopamine receptors. Dopamine antagonists have been used for several other clinical purposes including as ANTIEMETICS, in the treatment of Tourette syndrome, and for hiccup. Dopamine receptor blockade is associated with NEUROLEPTIC MALIGNANT SYNDROME.
An ergot derivative that acts as an agonist at dopamine D2 receptors (DOPAMINE AGONISTS). It may also act as an antagonist at dopamine D1 receptors, and as an agonist at some serotonin receptors (SEROTONIN AGONISTS).
A thiazole derivative and atypical ANTIPSYCHOTIC AGENT that functions as a DOPAMINE D2 RECEPTOR ANTAGONIST; SEROTONIN 5-HT2 RECEPTOR ANTAGONIST, serotonin 5-HT7 receptor antagonist, and antagonist of the adrenergic α2A and α2C receptors, as well as a partial SEROTONIN 5-HT1A RECEPTOR AGONIST. It is used in the treatment of SCHIZOPHRENIA and BIPOLAR DISORDER.
Drugs that bind to and activate dopamine receptors.
A dibenzothiazepine and ANTIPSYCHOTIC AGENT that targets the SEROTONIN 5-HT2 RECEPTOR; HISTAMINE H1 RECEPTOR, adrenergic alpha1 and alpha2 receptors, as well as the DOPAMINE D1 RECEPTOR and DOPAMINE D2 RECEPTOR. It is used in the treatment of SCHIZOPHRENIA; BIPOLAR DISORDER and DEPRESSIVE DISORDER.
Within medicine, nutrition (the study of food and the effect of its components on the body) has many different roles. Appropriate nutrition can help prevent certain diseases, or treat others. In critically ill patients, artificial feeding by tubes need t...