Highly Selective Dopamine D<sub>3</sub> Receptor Antagonists with Arylated Diazaspiro Alkane Cores

Reilly, Sean W.; Griffin, Suzy A.; Taylor, Michelle; Sahlholm, Kristoffer; Weng, Chi Chang; Xu, Kuiying; Jacome, Daniel A.; Luedtke, Robert T.; Mach, Robert H.

doi:10.1021/acs.jmedchem.7b01248

Cited by 33 publications

(38 citation statements)

References 37 publications

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“…the Murraya alkaloids 8 (Figure 4b). 34 Connection of two fragments through only one atom in a point-on-point manner will result in the formation of a spirocyclic centre such as reported for the diazaspirodecane core of selective dopamine D3 receptor antagonists 9, 35 (Figure 4c) and the NP (−)-horsfiline, 10. 36 Two fragments may share three or more common atoms, forming a bridged bicyclic scaffold (Figure 4d), as for instance in the chromopynones 1, and in the NP sespenine, 11.…”

Section: Structural Analyses Of Pseudo-natural Productsmentioning

confidence: 97%

Principle and design of pseudo-natural products

et al. 2020

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Natural products (NPs) are a significant source of inspiration towards the discovery of new bioactive compounds based on novel molecular scaffolds. However, there are currently only a small number of guiding synthetic strategies available to generate novel NP-inspired scaffolds, limiting both the number and types of compounds accessible. In this Perspective, we discuss a design approach for the preparation of biologically relevant small molecule libraries, harnessing the unprecedented combination of NP-derived fragments as an overarching strategy for the synthesis of new bioactive compounds. These novel 'pseudo-natural product' classes retain the biological relevance of NPs, yet exhibit structures and bioactivities not accessible to nature or through the use of existing design strategies. We also analyse selected pseudo-NP libraries using chemoinformatic tools, to assess their molecular shape diversity and properties. To facilitate the exploration of biologically relevant chemical space, we have identified design principles and connectivity patterns that would provide access to unprecedented pseudo-NP classes, offering new opportunities for bioactive small molecule discovery. Main textThe search for small molecules with novel molecular scaffolds that display unprecedented or unexpected biological activity greatly benefits from insights gained from compound classes that are biologically relevant by definition, such as natural products (NPs). NPs have served as an inspiration and resource in drug discovery and chemical biology 1 and constitute chemical matter pre-validated by evolution. 2 Libraries based on natural product structure or more relaxed chemical and structural considerations have been developed through different approaches. At one end of the spectrum NP-derived compound collections may be synthesised directly from readily available NPs, e.g. by derivatisations at pre-existing reactive sites, and by ringdistortion and/or -modification approaches ("complexity to diversity"; CtD) as first demonstrated by Hergenrother. 3,4 For instance, abietic acid was converted into a chemically diverse collection of complex compounds by means of 3-6 transformations, including ring opening-, expansion-and contraction sequences 4 (Figure 1a), whilst ring-distortion of the alkaloid quinidine yielded novel inhibitors of autophagy. 5 In an alternative approach complex polycyclic scaffolds that exhibit NP characteristics and properties are directly synthesised and distorted. For instance, tropane-containing compounds delivered multiple new scaffolds not found within NPs, several of which were found to be novel bromodomain binders. 6

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Section: Structural Analyses Of Pseudo-natural Productsmentioning

confidence: 97%

Principle and design of pseudo-natural products

et al. 2020

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“…Some representatives of diazaspiro alkane [ 142 ] and 6-methoxy-1,2,3,4-tetrahydroquinolin-7-ol derivatives [ 143 ] showed high affinity (Ki < 20 nM) and high selectivity (D2R/D3R ratio: 200–1000) antagonists for D3R under in vitro conditions but the pharmacokinetic properties or their in vivo actions were not reported.…”

Section: D3r Ligandsmentioning

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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“…Our previous work has shown these piperazine alternatives to be effective in alleviating off-target promiscuity and inducing unique protein-ligand interactions. 30 Here, were report the synthesis and the pharmacological profiling of 16b - 17b , utilizing in vitro and computational modeling. This work afforded best in class compound, 10e , an olaparib congener with nanomolar PARP-1 affinity and poor DNA damaging properties, which can be explored as a potential therapeutic for inflammation or neurodegeneration applications where cytotoxicity is not desired.…”

Section: Introductionmentioning

confidence: 99%

Examination of Diazaspiro Cores as Piperazine Bioisosteres in the Olaparib Framework Shows Reduced DNA Damage and Cytotoxicity

et al. 2018

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Development of poly(ADP-ribose) polymerase inhibitors (PARPi's) continues to be an attractive area of research due to synthetic lethality in DNA repair deficient cancers; however, PARPi's also have potential as therapeutics to prevent harmful inflammation. We investigated the pharmacological impact of incorporating spirodiamine motifs into the phthalazine architecture of FDA approved PARPi olaparib. Synthesized analogues were screened for PARP-1 affinity, enzyme specificity, catalytic inhibition, DNA damage, and cytotoxicity. This work led to the identification of 10e (12.6 ± 1.1 nM), which did not induce DNA damage at similar drug concentrations as olaparib. Interestingly, several worst in class compounds with low PARP-1 affinity, including 15b (4397 ± 1.1 nM), induced DNA damage at micromolar concentrations, which can explain the cytotoxicity observed in vitro. This work provides further evidence that high affinity PARPi's can be developed without DNA damaging properties offering potential new drugs for treating inflammatory related diseases.

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Highly Selective Dopamine D₃ Receptor Antagonists with Arylated Diazaspiro Alkane Cores

Cited by 33 publications

References 37 publications

Principle and design of pseudo-natural products

Principle and design of pseudo-natural products

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

Examination of Diazaspiro Cores as Piperazine Bioisosteres in the Olaparib Framework Shows Reduced DNA Damage and Cytotoxicity

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Highly Selective Dopamine D3 Receptor Antagonists with Arylated Diazaspiro Alkane Cores

Cited by 33 publications

References 37 publications

Principle and design of pseudo-natural products

Principle and design of pseudo-natural products

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

Examination of Diazaspiro Cores as Piperazine Bioisosteres in the Olaparib Framework Shows Reduced DNA Damage and Cytotoxicity

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Highly Selective Dopamine D₃ Receptor Antagonists with Arylated Diazaspiro Alkane Cores