Synthesis and Pharmacological Characterization of Novel trans-Cyclopropylmethyl-Linked Bivalent Ligands That Exhibit Selectivity and Allosteric Pharmacology at the Dopamine D3 Receptor (D3R)

Kumar, Vivek; Moritz, Amy E.; Keck, Thomas M.; Bonifazi, Alessandro; Ellenberger, Michael P.; Sibley, Christopher D.; Free, R. Benjamin; Shi, Lei; Lane, J. Robert; Sibley, David R.; Newman, Amy Hauck

doi:10.1021/acs.jmedchem.6b01688

Cited by 43 publications

(102 citation statements)

References 53 publications

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“…compound 19 ) [46]. The global selectivity of this series has not yet been fully established, but these data highlight the usefulness of structure-guided medicinal chemistry efforts in finding selective compounds; particularly focusing on elongated bivalent compounds that engage secondary binding pockets in the D 3 R as a bitopic mechanism of engendering selectivity [49].…”

Section: D3r Selective Antagonistsmentioning

confidence: 99%

Advances and challenges in the search for D2 and D3 dopamine receptor-selective compounds

Moritz

Free

Sibley

2018

Cellular Signalling

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Compounds that target D2-like dopamine receptors (DRs) are currently used as therapeutics for several neuropsychiatric disorders including schizophrenia (antagonists) and Parkinson's disease (agonists). However, as the DR and DR subtypes are highly homologous, creating compounds with sufficient subtype-selectivity as well as drug-like properties for therapeutic use has proved challenging. This review summarizes the progress that has been made in developing DR- or DR-selective antagonists and agonists, and also describes the experimental conditions that need to be considered when determining the selectivity of a given compound, as apparent selectivity can vary widely depending on assay conditions. Future advances in this field may take advantage of currently available structural data to target alternative secondary binding sites through creating bivalent or bitopic chemical structures. Alternatively, the use of high-throughput screening techniques to identify novel scaffolds that might bind to the DR or DR in areas other than the highly conserved orthosteric site, such as allosteric sites, followed by iterative medicinal chemistry will likely lead to exceptionally selective compounds in the future. More selective compounds will provide a better understanding of the normal and pathological functioning of each receptor subtype, as well as offer the potential for improved therapeutics.

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Section: D3r Selective Antagonistsmentioning

confidence: 99%

Advances and challenges in the search for D2 and D3 dopamine receptor-selective compounds

Moritz

Free

Sibley

2018

Cellular Signalling

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“…Taken together, these results strongly suggest that SB269,652 behaves as a negative allosteric modulator at dopamine D 2 and dopamine D 3 receptors -the first to be identified. The allosteric nature of this compound was subsequently confirmed by Lane et al (2014); Shonberg et al, (2015); Mistry et al (2015) for dopamine D 2 receptor and by Kumar et al (2017), for dopamine D 3 receptor, and now SB269,652 has become a leading compound in the synthesis of new allosteric drugs (Rossi et al, 2017).…”

Section: Introductionmentioning

confidence: 88%

Distinctive binding properties of the negative allosteric modulator, [ 3 H]SB269,652, at recombinant dopamine D 3 receptors

Fasciani

Pietrantoni

Rossi

et al. 2018

European Journal of Pharmacology

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Recently, employing radioligand displacement and functional coupling studies, we demonstrated that SB269,652 (N-[(1r,4r)-4-[2-(7-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-1H-indole-2-carboxamide) interacts in an atypical manner with dopamine D receptor displaying a unique profile reminiscent of a negative allosteric ligand. Here, we characterized the binding of radiolabelled [H]SB269,652 to human dopamine D receptor stably expressed in Chinese Hamster Ovary cells. Under saturating conditions, SB269,652 showed a KD value of ≈ 1nM. Consistent with high selectivity for human dopamine D receptor, [H]SB269,652 binding was undetectable in cells expressing human dopamine D, D or D receptors and absent in synaptosomes from dopamine D receptor knockout vs. wild-type mice. In contrast to saturation binding experiments, the dissociation kinetics of [H]SB269,652 from human dopamine D receptors initiated with an excess of unlabelled ligand were best fitted by a bi-exponential binding model. Supporting the kinetic data, competition experiments with haloperidol, S33084 (a dopamine D receptor antagonist) or dopamine, were best described by a two-site model. In co-transfection experiments binding of SB269,652 to dopamine D receptor was able to influence the functional coupling of dopamine D receptor, supporting the notion that SB269,652 is a negative allosteric modulator across receptor dimers. However, because SB269,652 decreases the rate of [H]nemonapride dissociation, the present data suggest that SB269,652 behaves as a bitopic antagonist at unoccupied dopamine D receptor, binding simultaneously to both orthosteric and allosteric sites, and as a pure negative allosteric modulator when receptors are occupied and it can solely bind to the allosteric site.

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“…During the last few years, optimization of the structure of SB269652 led to more potent allosteric modulators for D 2 and D 3 receptors. An interesting approach was used by Kumar et al (2017) [ 78 ], who synthesized a series of molecules where the primary and secondary pharmacophores were derived from SB269652 and SB277011A (a competitive antagonist), whose structural similarity and pharmacological disparity provided the perfect templates for SAR investigation. Incorporating a trans-cyclopropylmethyl linker between the 7CN-THIQ and the 1H-indole-2-carboxamide moieties and manipulating linker length, the researchers identified two bivalent noncompetitive D 3 -selective antagonists, 18a and 25a [ 78 ].…”

Section: Sb269652—a Prototypical Negative Allosteric Modulator Ofmentioning

confidence: 99%

Allosteric Modulators of G Protein-Coupled Dopamine and Serotonin Receptors: A New Class of Atypical Antipsychotics

et al. 2020

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Schizophrenia was first described by Emil Krapelin in the 19th century as one of the major mental illnesses causing disability worldwide. Since the introduction of chlorpromazine in 1952, strategies aimed at modifying the activity of dopamine receptors have played a major role for the treatment of schizophrenia. The introduction of atypical antipsychotics with clozapine broadened the range of potential targets for the treatment of this psychiatric disease, as they also modify the activity of the serotoninergic receptors. Interestingly, all marketed drugs for schizophrenia bind to the orthosteric binding pocket of the receptor as competitive antagonists or partial agonists. In recent years, a strong effort to develop allosteric modulators as potential therapeutic agents for schizophrenia was made, mainly for the several advantages in their use. In particular, the allosteric binding sites are topographically distinct from the orthosteric pockets, and thus drugs targeting these sites have a higher degree of receptor subunit specificity. Moreover, “pure” allosteric modulators maintain the temporal and spatial fidelity of native orthosteric ligand. Furthermore, allosteric modulators have a “ceiling effect”, and their modulatory effect is saturated above certain concentrations. In this review, we summarize the progresses made in the identification of allosteric drugs for dopamine and serotonin receptors, which could lead to a new generation of atypical antipsychotics with a better profile, especially in terms of reduced side effects.

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Synthesis and Pharmacological Characterization of Novel trans-Cyclopropylmethyl-Linked Bivalent Ligands That Exhibit Selectivity and Allosteric Pharmacology at the Dopamine D₃ Receptor (D₃R)

Cited by 43 publications

References 53 publications

Advances and challenges in the search for D2 and D3 dopamine receptor-selective compounds

Advances and challenges in the search for D2 and D3 dopamine receptor-selective compounds

Distinctive binding properties of the negative allosteric modulator, [ 3 H]SB269,652, at recombinant dopamine D 3 receptors

Allosteric Modulators of G Protein-Coupled Dopamine and Serotonin Receptors: A New Class of Atypical Antipsychotics

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