Potent haloperidol derivatives covalently binding to the dopamine D2 receptor

Schwalbe, Tobias; Kaindl, Jonas; Hübner, Harald; Gmeiner, Peter

doi:10.1016/j.bmc.2017.06.034

Cited by 11 publications

(4 citation statements)

References 40 publications

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“…For example, covalent trapping of the β2 adrenergic receptor, equipped with an engineered cysteine (H93C), by the disulfide-based ligand FAUC50 ( 82 , Figure B) enabled the first X-ray crystallographic structure determination of this GPCR in an agonist-bound state . Although many medicinal chemistry campaigns, especially in academia, have exploited disulfide formation for covalent cysteine targeting (for some recent examples, see refs − ), it remains questionable if this linkage strategy is suitable for targeted covalent inhibition in vivo due to the complexity of physiological thiol–disulfide equilibria and redox systems. , Therefore, no further discussion is provided.…”

Section: Targeting the Cysteine Side Chainmentioning

confidence: 99%

Emerging and Re-Emerging Warheads for Targeted Covalent Inhibitors: Applications in Medicinal Chemistry and Chemical Biology

2018

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Targeted covalent inhibitors (TCIs) are designed to bind poorly conserved amino acids by means of reactive groups, the so-called warheads. Currently, targeting noncatalytic cysteine residues with acrylamides and other α,β-unsaturated carbonyl compounds is the predominant strategy in TCI development. The recent ascent of covalent drugs has stimulated considerable efforts to characterize alternative warheads for the covalent-reversible and irreversible engagement of noncatalytic cysteine residues as well as other amino acids. This Perspective article provides an overview of warheadsbeyond α,β-unsaturated amidesrecently used in the design of targeted covalent ligands. Promising reactive groups that have not yet demonstrated their utility in TCI development are also highlighted. Special emphasis is placed on the discussion of reactivity and of case studies illustrating applications in medicinal chemistry and chemical biology.

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Section: Targeting the Cysteine Side Chainmentioning

confidence: 99%

Emerging and Re-Emerging Warheads for Targeted Covalent Inhibitors: Applications in Medicinal Chemistry and Chemical Biology

2018

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“…81 Therefore, intrinsically electrophilic covalent ligands gained attraction in the field of GPCRs and were described for e.g. opioid receptors 81,83,84 , β 1 -and β 2 -adreneroceptors [85][86][87] , the histamine H 3 receptor 88 , the dopamine D 2 receptor 89 and the muscarinic acetylcholine M 2 receptor 90 . They have already been involved in the early identification of GPCR binding sites and in investigations on the function the detection of low-level receptor binding.…”

Section: Bivalent Ligandsmentioning

confidence: 99%

UR-DEBa242: A Py-5-Labeled Fluorescent Multipurpose Probe for Investigations on the Histamine H₃ and H₄ Receptors

et al. 2020

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Oral presentationsBartole, E.; Littmann, T.; Bernhardt, G.; Buschauer, A. "2,4-Diaminopyrimidines: towards molecular tools for investigations on human and rodent histamine H 4 receptors." Mid-term evaluation event of the GRK 1910 by the "Deutsche Forschungsgemeinschaft" (Regensburg, 2017) Bartole, E.; Littmann, T.; Bernhardt, G.; Buschauer, A. "2,4-Diaminopyrimidines: towards molecular tools for investigations on human and rodent histamine H 4 receptors." 1 st Joint meeting of the European and Japanese Histamine Research Societies (Amsterdam, 2017) Bartole, E.; Bernhardt, G.; Buschauer, A. "Molecular tools for the investigation of GPCR orthologues: the histamine H 4 receptor as an example." Christmas Colloquium 2016 of the

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“…The importance of dopaminergic pathways and receptor modulators in the control of neurodegenerative diseases led to the development of drugs such as the classical typical antipsychotic haloperidol ( 1 ), a D 2 receptor antagonist (Ki = 0.89 nM) [ 19 , 20 ], and the atypical antipsychotics aripiprazole ( 2 ) (Ki D 2 = 0.34 nM; Ki D 3 = 0.8 nM) and cariprazine ( 3 ) (Ki D 3 = 0.085 nM; Ki D 2 = 0.49 nM), as partial agonists of D 2 and D 3 receptors [ 21 , 22 , 23 , 24 , 25 , 26 ], approved for the treatment of schizophrenia and bipolar disorder ( Figure 1 ).…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Pharmacological Evaluation of Novel Conformationally Restricted N-arylpiperazine Derivatives Characterized as D2/D3 Receptor Ligands, Candidates for the Treatment of Neurodegenerative Diseases

et al. 2022

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Most neurodegenerative diseases are multifactorial, and the discovery of several molecular mechanisms related to their pathogenesis is constantly advancing. Dopamine and dopaminergic receptor subtypes are involved in the pathophysiology of several neurological disorders, such as schizophrenia, depression and drug addiction. For this reason, the dopaminergic system and dopamine receptor ligands play a key role in the treatment of such disorders. In this context, a novel series of conformationally restricted N-arylpiperazine derivatives (5a–f) with a good affinity for D2/D3 dopamine receptors is reported herein. Compounds were designed as interphenylene analogs of the drugs aripiprazole (2) and cariprazine (3), presenting a 1,3-benzodioxolyl subunit as a ligand of the secondary binding site of these receptors. The six new N-arylpiperazine compounds were synthesized in good yields by using classical methodologies, and binding and guanosine triphosphate (GTP)-shift studies were performed. Affinity values below 1 μM for both target receptors and distinct profiles of intrinsic efficacy were found. Docking studies revealed that Compounds 5a–f present a different binding mode with dopamine D2 and D3 receptors, mainly as a consequence of the conformational restriction imposed on the flexible spacer groups of 2 and 3.

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Potent haloperidol derivatives covalently binding to the dopamine D2 receptor

Cited by 11 publications

References 40 publications

Emerging and Re-Emerging Warheads for Targeted Covalent Inhibitors: Applications in Medicinal Chemistry and Chemical Biology

Emerging and Re-Emerging Warheads for Targeted Covalent Inhibitors: Applications in Medicinal Chemistry and Chemical Biology

UR-DEBa242: A Py-5-Labeled Fluorescent Multipurpose Probe for Investigations on the Histamine H₃ and H₄ Receptors

Design, Synthesis and Pharmacological Evaluation of Novel Conformationally Restricted N-arylpiperazine Derivatives Characterized as D2/D3 Receptor Ligands, Candidates for the Treatment of Neurodegenerative Diseases

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Potent haloperidol derivatives covalently binding to the dopamine D2 receptor

Cited by 11 publications

References 40 publications

Emerging and Re-Emerging Warheads for Targeted Covalent Inhibitors: Applications in Medicinal Chemistry and Chemical Biology

Emerging and Re-Emerging Warheads for Targeted Covalent Inhibitors: Applications in Medicinal Chemistry and Chemical Biology

UR-DEBa242: A Py-5-Labeled Fluorescent Multipurpose Probe for Investigations on the Histamine H3 and H4 Receptors

Design, Synthesis and Pharmacological Evaluation of Novel Conformationally Restricted N-arylpiperazine Derivatives Characterized as D2/D3 Receptor Ligands, Candidates for the Treatment of Neurodegenerative Diseases

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Product

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UR-DEBa242: A Py-5-Labeled Fluorescent Multipurpose Probe for Investigations on the Histamine H₃ and H₄ Receptors