Development of Novel 1,2,3,4‐Tetrahydroisoquinoline Derivatives and Closely Related Compounds as Potent and Selective Dopamine D3 Receptor Ligands

doi:10.1002/cbic.200300784

Paper

Development of Novel 1,2,3,4‐Tetrahydroisoquinoline Derivatives and Closely Related Compounds as Potent and Selective Dopamine D3 Receptor Ligands

Published Apr 2, 2004 · Ulrich R. Mach, Anneke E. Hackling, S. Perachon

ChemBioChem

Q1 SJR score

82

Citations

1

Influential Citations

Full textSemantic Scholar

Abstract

Based on N‐alkylated 1,2,3,4‐tetrahydroisoquinoline derivatives, which are structurally related to the partial agonist BP 897, a series of novel, selective dopamine D3 receptor antagonists has been synthesised. Derivatisation included changes in the arylamide moiety and the tetrahydroisoquinoline substructure leading to compounds with markedly improved selectivities and affinities in the low nanomolar concentration range. From the 55 structures presented here, (E)‐3‐(4‐iodophenyl)‐N‐(4‐(1,2,3,4‐tetrahydroisoquinolin‐2‐yl)butyl)acrylamide (51) has high affinity (Ki(hD3)=12 nM) and a 123‐fold preference for the D3 receptor relative to the D2 receptor subtype. Its pharmacological profile offers the prospect of a novel radioligand as a tool for various dopamine D3‐receptor‐related in vitro and in vivo investigations.

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Study Snapshot

Novel 1,2,3,4-tetrahydroisoquinoline derivatives show improved selectivity and affinities for dopamine D3 receptors, offering potential as tools for in vitro and in vivo investigations.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Development of Novel 1,2,3,4‐Tetrahydroisoquinoline Derivatives and Closely Related Compounds as Potent and Selective Dopamine D3 Receptor Ligands

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References

Progress in developing D3 dopamine receptor ligands as potential therapeutic agents for neurological and neuropsychiatric disorders.

Recent advances in D3 receptor biochemistry and pharmacology suggest that altered D3 receptor function contributes to various CNS disorders, including schizophrenia, Parkinson's Disease, and substance abuse.

Dopamine D3 Receptor Ligands with Antagonist Properties

Dopamine D3 receptor antagonists show potential for improved treatment of psychosis like schizophrenia and drug abuse, while partial agonists show benefits in Parkinson's disease and drug addiction.

Synthesis and Structure–Activity Relationship of the Isoindolinyl Benzisoxazolpiperidines as Potent, Selective, and Orally Active Human Dopamine D4 Receptor Antagonists

Isoindolinyl benzisoxazolpiperidines are potent, selective, and orally active human dopamine D4 receptor antagonists with greater than 100-fold selectivity over D2 and the 1 adrenoreceptor.

Interactive SAR studies: rational discovery of super-potent and highly selective dopamine D3 receptor antagonists and partial agonists.

This interactive drug discovery process led to the discovery of super-potent and highly selective dopamine D3 receptor antagonists and partial agonists, with benzothiophenes 3c and 3d showing outstanding affinity and subtype selectivity.

Identification of the dopamine autoreceptor in the guinea‐pig retina as D2 receptor using novel subtype‐selective antagonists

The dopamine autoreceptor in the guinea-pig retina is a D2 receptor, and novel antagonists ST-148 and ST-198 show improved selectivity for D2 and D3 receptors compared to haloperidol and (S)-nafadotride.

Citations

Base-mediated [4 + 3] annulation of α-halogen hydroximate with o-QMs: Facile access to 1, 4-benzoxazepine scaffold

This study developed a facile approach to 1, 4-benzoxazepine from -halogen hydroximate and o-QMs, yielding moderate to excellent products under mild reaction conditions.

Neurobiological and Pharmacological Perspectives of D3 Receptors in Parkinson’s Disease

D3 receptors play a crucial role in Parkinson's disease and may mediate some of the effects of dopamine replacement therapy, but their role in PD remains unclear.

Iridium(III)-Catalyzed C(3)-H Alkylation of Isoquinolines via Metal Carbene Migratory Insertion.

Iridium(III)-catalyzed C(3)-H alkylation of isoquinolines via metal carbene migratory insertion leads to the formation of synthetically viable isoquinoline derivatives with immense potentials.

Structure-activity relationship studies for the development of inhibitors of murine adipose triglyceride lipase (ATGL).

Atglistatin, a specific inhibitor of murine ATGL, shows potential in lowering circulating fatty acid concentrations and counteracting the development of insulin resistance and non-alcoholic fatty liver disease.

From Wood to Tetrahydro-2-benzazepines in Three Waste-Free Steps: Modular Synthesis of Biologically Active Lignin-Derived Scaffolds

This study presents a waste-free strategy for synthesis of biologically active molecules from wood, potentially benefiting the pharmaceutical industry and increasing the economic feasibility of lignocellulosic biorefineries.

Transition Metal Free One-Pot Tandem Synthesis of 3-Ketoisoquinolines from Aldehydes and Phenacyl azides.

This efficient one-pot strategy efficiently synthesizes 3-keto-isoquinolines from readily accessible 2-(formylphenyl)acrylates and phenacyl azides, yielding various 3-keto-isoquinolines in good yields.

Development of Novel 1,2,3,4‐Tetrahydroisoquinoline Derivatives and Closely Related Compounds as Potent and Selective Dopamine D3 Receptor Ligands

Sign up to use Study Snapshot

References

Progress in developing D3 dopamine receptor ligands as potential therapeutic agents for neurological and neuropsychiatric disorders.

Recent advances in D3 receptor biochemistry and pharmacology suggest that altered D3 receptor function contributes to various CNS disorders, including schizophrenia, Parkinson's Disease, and substance abuse.

Dopamine D3 Receptor Ligands with Antagonist Properties

Dopamine D3 receptor antagonists show potential for improved treatment of psychosis like schizophrenia and drug abuse, while partial agonists show benefits in Parkinson's disease and drug addiction.

Synthesis and Structure–Activity Relationship of the Isoindolinyl Benzisoxazolpiperidines as Potent, Selective, and Orally Active Human Dopamine D4 Receptor Antagonists

Isoindolinyl benzisoxazolpiperidines are potent, selective, and orally active human dopamine D4 receptor antagonists with greater than 100-fold selectivity over D2 and the 1 adrenoreceptor.

Interactive SAR studies: rational discovery of super-potent and highly selective dopamine D3 receptor antagonists and partial agonists.

This interactive drug discovery process led to the discovery of super-potent and highly selective dopamine D3 receptor antagonists and partial agonists, with benzothiophenes 3c and 3d showing outstanding affinity and subtype selectivity.

Identification of the dopamine autoreceptor in the guinea‐pig retina as D2 receptor using novel subtype‐selective antagonists

The dopamine autoreceptor in the guinea-pig retina is a D2 receptor, and novel antagonists ST-148 and ST-198 show improved selectivity for D2 and D3 receptors compared to haloperidol and (S)-nafadotride.

Citations

Base-mediated [4 + 3] annulation of α-halogen hydroximate with o-QMs: Facile access to 1, 4-benzoxazepine scaffold

This study developed a facile approach to 1, 4-benzoxazepine from -halogen hydroximate and o-QMs, yielding moderate to excellent products under mild reaction conditions.

Neurobiological and Pharmacological Perspectives of D3 Receptors in Parkinson’s Disease

D3 receptors play a crucial role in Parkinson's disease and may mediate some of the effects of dopamine replacement therapy, but their role in PD remains unclear.

Iridium(III)-Catalyzed C(3)-H Alkylation of Isoquinolines via Metal Carbene Migratory Insertion.

Iridium(III)-catalyzed C(3)-H alkylation of isoquinolines via metal carbene migratory insertion leads to the formation of synthetically viable isoquinoline derivatives with immense potentials.

Structure-activity relationship studies for the development of inhibitors of murine adipose triglyceride lipase (ATGL).

Atglistatin, a specific inhibitor of murine ATGL, shows potential in lowering circulating fatty acid concentrations and counteracting the development of insulin resistance and non-alcoholic fatty liver disease.

From Wood to Tetrahydro-2-benzazepines in Three Waste-Free Steps: Modular Synthesis of Biologically Active Lignin-Derived Scaffolds

This study presents a waste-free strategy for synthesis of biologically active molecules from wood, potentially benefiting the pharmaceutical industry and increasing the economic feasibility of lignocellulosic biorefineries.

Transition Metal Free One-Pot Tandem Synthesis of 3-Ketoisoquinolines from Aldehydes and Phenacyl azides.

This efficient one-pot strategy efficiently synthesizes 3-keto-isoquinolines from readily accessible 2-(formylphenyl)acrylates and phenacyl azides, yielding various 3-keto-isoquinolines in good yields.

Base-mediated [4 + 3] annulation of α-halogen hydroximate with o-QMs: Facile access to 1, 4-benzoxazepine scaffold