Molecular Determinants of the Intrinsic Efficacy of the Antipsychotic Aripiprazole

Herenbrink, Carmen Klein; Verma, Ravi Kumar; Lim, Herman D.; Kopinathan, Anitha; Keen, Alastair C.; Shonberg, Jeremy; Draper-Joyce, Christopher J; Scammells, Peter J.; Christopoulos, Arthur; Javitch, Jonathan A.; Capuano, Ben; Shi, Lei; Lane, J. Robert

doi:10.1021/acschembio.9b00342

Cited by 20 publications

(26 citation statements)

References 49 publications

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“…Previous investigations suggested a crucial role for residues V91, L94, and E95 in contacting the secondary pharmacophore of bivalent D 2 R ligands, including SV-III-130. 16 , 19 In addition, W100A in extracellular loop 1 is located at the extracellular boundary of the secondary binding pocket and has been shown to affect bivalent ligand affinity and to adopt different conformations depending on the nature of the bound ligand. 13 , 27 To investigate the role of the secondary binding pocket in shaping SV-III-130 binding kinetics and insurmountability, V91, L94, E95, and W100 were individually mutated to alanine.…”

Section: Resultsmentioning

confidence: 99%

Ligand with Two Modes of Interaction with the Dopamine D₂ Receptor–An Induced-Fit Mechanism of Insurmountable Antagonism

Ågren

Zeberg

Stępniewski

et al. 2020

ACS Chem. Neurosci.

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A solid understanding of the mechanisms governing ligand binding is crucial for rational design of therapeutics targeting the dopamine D 2 receptor (D 2 R). Here, we use G protein-coupled inward rectifier potassium (GIRK) channel activation in Xenopus oocytes to measure the kinetics of D 2 R antagonism by a series of aripiprazole analogues, as well as the recovery of dopamine (DA) responsivity upon washout. The aripiprazole analogues comprise an orthosteric and a secondary pharmacophore and differ by the length of the saturated carbon linker joining these two pharmacophores. Two compounds containing 3- and 5-carbon linkers allowed for a similar extent of recovery from antagonism in the presence of 1 or 100 μM DA (>25 and >90% of control, respectively), whereas recovery was less prominent (∼20%) upon washout of the 4-carbon linker compound, SV-III-130, both with 1 and 100 μM DA. Prolonging the coincubation time with SV-III-130 further diminished recovery. Curve-shift experiments were consistent with competition between SV-III-130 and DA. Two mutations in the secondary binding pocket (V91A and E95A) of D 2 R decreased antagonistic potency and increased recovery from SV-III-130 antagonism, whereas a third mutation (L94A) only increased recovery. Our results suggest that the secondary binding pocket influences recovery from inhibition by the studied aripiprazole analogues. We propose a mechanism, supported by in silico modeling, whereby SV-III-130 initially binds reversibly to the D 2 R, after which the drug-receptor complex undergoes a slow transition to a second ligand-bound state, which is dependent on secondary binding pocket integrity and irreversible during the time frame of our experiments.

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Section: Resultsmentioning

confidence: 99%

Ligand with Two Modes of Interaction with the Dopamine D₂ Receptor–An Induced-Fit Mechanism of Insurmountable Antagonism

Ågren

Zeberg

Stępniewski

et al. 2020

ACS Chem. Neurosci.

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“…More comprehensive analyses of the D2R mutants by collecting full ONC201 doseresponse curves using Go activation and cAMP inhibition assays showed that mutations of four specific residues, V91 2.61 , E95 2.65 , Y192 5.41 , and I397 6.59 , produced the most severe impact on ONC201's ability to antagonize dopamine-stimulated signaling. Notably, two of these residues, V91 2.61 and E95 2.65 , reside within a SBP formed by the interface between TMs 2 and 7 and have been shown to be involved in allosteric modulation of the D2R by bitopic and negative allosteric modulators (NAMs) (Draper-Joyce et al, 2018;Klein Herenbrink et al, 2019;Verma et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Characterization of the Imipridone Anticancer Drug ONC201 Reveals a Negative Allosteric Mechanism of Action at the D₂Dopamine Receptor

et al. 2021

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“…Most of the published D3R selective ligands are common in pharmacophore consisting of a head group, which is positively charged and bear an aromatic ring, and a heteroaromatic tail connected by an apolar linker region ( Figure 3 ) [ 79 ]. This heteroaromatic tail which binds to the secondary binding pocket of the D3R is responsible for the high selectivity over the D2R (i.e., K i,D2 /K i,D3 > 100) and can fine-tune the functional character of the ligands [ 80 ]. The linker may also be important in this regard [ 81 ].…”

Section: Structure Of Dopamine D3rmentioning

confidence: 99%

Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders

et al. 2021

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Dopamine (DA), as one of the major neurotransmitters in the central nervous system (CNS) and periphery, exerts its actions through five types of receptors which belong to two major subfamilies such as D1-like (i.e., D1 and D5 receptors) and D2-like (i.e., D2, D3 and D4) receptors. Dopamine D3 receptor (D3R) was cloned 30 years ago, and its distribution in the CNS and in the periphery, molecular structure, cellular signaling mechanisms have been largely explored. Involvement of D3Rs has been recognized in several CNS functions such as movement control, cognition, learning, reward, emotional regulation and social behavior. D3Rs have become a promising target of drug research and great efforts have been made to obtain high affinity ligands (selective agonists, partial agonists and antagonists) in order to elucidate D3R functions. There has been a strong drive behind the efforts to find drug-like compounds with high affinity and selectivity and various functionality for D3Rs in the hope that they would have potential treatment options in CNS diseases such as schizophrenia, drug abuse, Parkinson’s disease, depression, and restless leg syndrome. In this review, we provide an overview and update of the major aspects of research related to D3Rs: distribution in the CNS and periphery, signaling and molecular properties, the status of ligands available for D3R research (agonists, antagonists and partial agonists), behavioral functions of D3Rs, the role in neural networks, and we provide a summary on how the D3R-related drug research has been translated to human therapy.

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Molecular Determinants of the Intrinsic Efficacy of the Antipsychotic Aripiprazole

Cited by 20 publications

References 49 publications

Ligand with Two Modes of Interaction with the Dopamine D₂ Receptor–An Induced-Fit Mechanism of Insurmountable Antagonism

Ligand with Two Modes of Interaction with the Dopamine D₂ Receptor–An Induced-Fit Mechanism of Insurmountable Antagonism

Pharmacological Characterization of the Imipridone Anticancer Drug ONC201 Reveals a Negative Allosteric Mechanism of Action at the D₂Dopamine Receptor

Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders

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Molecular Determinants of the Intrinsic Efficacy of the Antipsychotic Aripiprazole

Cited by 20 publications

References 49 publications

Ligand with Two Modes of Interaction with the Dopamine D2 Receptor–An Induced-Fit Mechanism of Insurmountable Antagonism

Ligand with Two Modes of Interaction with the Dopamine D2 Receptor–An Induced-Fit Mechanism of Insurmountable Antagonism

Pharmacological Characterization of the Imipridone Anticancer Drug ONC201 Reveals a Negative Allosteric Mechanism of Action at the D2Dopamine Receptor

Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders

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Ligand with Two Modes of Interaction with the Dopamine D₂ Receptor–An Induced-Fit Mechanism of Insurmountable Antagonism

Ligand with Two Modes of Interaction with the Dopamine D₂ Receptor–An Induced-Fit Mechanism of Insurmountable Antagonism

Pharmacological Characterization of the Imipridone Anticancer Drug ONC201 Reveals a Negative Allosteric Mechanism of Action at the D₂Dopamine Receptor