1,2,4-Triazolyl Azabicyclo[3.1.0]hexanes: A New Series of Potent and Selective Dopamine D<sub>3</sub> Receptor Antagonists

Micheli, Fabrizio; Arista, Luca; Bonanomi, Giorgio; Blaney, Frank E.; Braggio, Simone; Capelli, Anna Maria; Checchia, Anna; Damiani, Federica; Di-Fabio, Romano; Fontana, Stefano; Gentile, Gabriella; Griffante, Cristiana; Hamprecht, Dieter; Marchioro, Carla; Mugnaini, Manolo; Piner, Jacqui; Ratti, Emiliangelo; Tedesco, Giovanna; Tarsi, Luca; Terreni, Silvia; Worby, Angela; Ashby, Charles R.; Heidbreder, Christian

doi:10.1021/jm901319p

Cited by 55 publications

(106 citation statements)

References 22 publications

Supporting

Mentioning

103

Contrasting

Order By: Relevance

“…GSK598809 is a selective dopamine D 3 receptor antagonist (Micheli et al, 2010;Searle et al, 2010) that has been tested in clinical trials for other indications (see http://clinicaltrials.gov/ct2/results? term5598809&Search5Search).…”

Section: Introductionmentioning

confidence: 99%

Dopamine D₃Receptor Antagonist (GSK598809) Potentiates the Hypertensive Effects of Cocaine in Conscious, Freely-Moving Dogs

Appel

Holmes

et al. 2015

J Pharmacol Exp Ther

View full text Add to dashboard Cite

The chronic and relapsing nature of addiction presents unique challenges for ensuring the safety of a potential medication. A patient may use cocaine, for example, while taking the medication or take more medication than prescribed. Thus, a potential medication must be safe and not exacerbate the effects of other substance use disorders. The US Food and Drug Administration has established guidelines recommending safety studies to investigate potential undesirable pharmacodynamic effects of a substance in relation to exposure in the therapeutic range and above. Hence, we assessed the interaction between this selective dopamine D 3 receptor antagonist and cocaine on hemodynamics and cardiac function in freely-moving, telemetered dogs before conducting a clinical trial. GSK598809 increased the hemodynamic effect of cocaine in this model. Thus, the increase in blood pressure after intravenous cocaine was greater in animals that had been pretreated with GSK598809 compared with vehicle. This finding suggests that GSK598809 in particular, and perhaps dopamine D 3 receptor antagonists as a class, may produce unacceptable cardiovascular risks as medications to treat cocaine use disorder.

show abstract

Section: Introductionmentioning

confidence: 99%

Dopamine D₃Receptor Antagonist (GSK598809) Potentiates the Hypertensive Effects of Cocaine in Conscious, Freely-Moving Dogs

Appel

Holmes

et al. 2015

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…No specific information on the synthesis of these SF 5 -compounds was provided (the CF 3 -analogues were synthesised in [119]). In general, the two series of compounds showed rather similar biological properties in vitro, as well as in vivo [120].…”

Section: Scheme 104mentioning

confidence: 99%

Synthetic chemistry and biological activity of pentafluorosulphanyl (SF5) organic molecules

Zanda

Altomonte

2012

Journal of Fluorine Chemistry

198

View full text Add to dashboard Cite

The pentafluorosulfanyl group (SF5) is a highly stable chemical function which has been attracting a great deal of interest owing to its peculiar chemical, structural, physicochemical and biological properties. Progress in the area of SF5-compounds has been somewhat hindered by the lack of straightforward lab-scale synthetic methods for introducing the SF5-group into organic molecules. However, recent synthetic progress, the availability of some SF5-building blocks from commercial suppliers and the discovery of interesting properties of SF5-substituted molecules in materials science, biology and drug discovery are giving new momentum to research in this fascinating area of fluorine chemistry. Synthesis, reactivity and biological properties of SF5-substituted organic molecules are herein reviewed with an emphasis on the work published after year 2000. Object *Cover Letter or Page containing Author DetailsAll of the referees' suggestions have been accepted, with the only exception of Referee's 2 point 5 "Reactions of ArylSF5 systems should be divided into sections …electrophilc substitutions, nucleophilic substitutions, reactions of diazo systems,…" because in that section the chemistry is inherently heterogeneous and we feel that such a subclassification would be very challenging to achieve and would make less homogeneous the discussion of the topic. Molecolare, via Mancinelli 7, 20131 Milano, Italy Synthesis, reactivity and biological properties of SF 5 -substituted organic molecules are reviewed in this article, with an emphasis on the work published in the last decade. *Graphical Abstract -Synopsis Highlights We review the synthesis of SF 5 -compounds, with an emphasis on work published after year 2000.  We review the reactivity of SF 5 -substituted organic molecules.  We review the biological properties of SF 5 -substituted drug candidates. Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK; e-mail: m.zanda@abdn.ac.uk b C.N.R.-Istituto di Chimica del Riconoscimento Molecolare, via Mancinelli 7, 20131 Milano, Italy AbstractThe pentafluorosulfanyl group (SF 5 ) is a highly stable chemical function which has been attracting a great deal of interest owing to its peculiar chemical, structural, physicochemical and biological properties. Progress in the area of SF 5 -compounds has been somewhat hindered by the lack of straightforward lab-scale synthetic methods for introducing the SF 5 -group into organic molecules. However, recent synthetic progress, the availability of some SF 5 -building blocks from commercial suppliers and the discovery of interesting properties of SF 5 -substituted molecules in materials science, biology and drug discovery are giving new momentum to research in this fascinating area of fluorine chemistry. Synthesis, reactivity and biological properties of SF 5 -substituted organic molecules are herein reviewed with an emphasis on the work published after year 2000.

show abstract

“…[3] Among the many research groups in this field, [2][3][4][5][6][7][8] GlaxoSmithKline (GSK) has actively contributed to the discovery of selective DA D 3 receptor antagonists. [9][10][11][12][13][14][15][16] Some recently disclosed compounds are shown in Figure 1. Derivative 5 belongs to a series of azabicyclo [3.1.0]hexanes that are endowed with very good in vitro affinity and selectivity, and which show a high degree of efficacy in preclinical models of drug addiction.…”

Section: Introductionmentioning

confidence: 99%

“…Derivative 5 belongs to a series of azabicyclo [3.1.0]hexanes that are endowed with very good in vitro affinity and selectivity, and which show a high degree of efficacy in preclinical models of drug addiction. [16] Herein we report studies carried out to understand the role of the sulfur atom in the "linker/spacer" [5,17] region of 5, together with the associated biological results. These changes, considering both the differences in the molecular orbitals and in the electronic content of the atoms involved, might have played a profound effect in the "antagonist region" [18] where the hydrogen bond acceptor sits.…”

Section: Introductionmentioning

confidence: 99%

“…[11,16] All NCEs were assayed for their agonist and antagonist properties with a functional GTPgS assay expressing the human DA D 3 receptor. Subsequently, 100-fold selectivity versus both the DA D 2 receptor (using D 2 functional assays) and the human ether-à-gogo (hERG) potassium channel (using the dofetilide binding assay) was requested in order to obtain a sufficiently broad preclinical therapeutic window to minimize potential adverse effects associated with these molecular targets.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Triazolyl Azabicyclo[3.1.0]hexanes: a Class of Potent and Selective Dopamine D₃ Receptor Antagonists

et al. 2010

Self Cite

View full text Add to dashboard Cite

Herein we report a detailed description of the structure-activity relationships for a novel series of "C-linked" 1,2,4-triazolylazabicyclo[3.1.0]hexanes. These derivatives are endowed with very high in vitro affinity and selectivity for the dopamine D(3) receptor. An optimization with respect to undesired affinity toward the hERG potassium channel is also reported. Members of this compound series also show excellent in vitro and in vivo pharmacokinetic properties.

show abstract

1,2,4-Triazolyl Azabicyclo[3.1.0]hexanes: A New Series of Potent and Selective Dopamine D₃ Receptor Antagonists

Cited by 55 publications

References 22 publications

Dopamine D₃Receptor Antagonist (GSK598809) Potentiates the Hypertensive Effects of Cocaine in Conscious, Freely-Moving Dogs

Dopamine D₃Receptor Antagonist (GSK598809) Potentiates the Hypertensive Effects of Cocaine in Conscious, Freely-Moving Dogs

Synthetic chemistry and biological activity of pentafluorosulphanyl (SF5) organic molecules

Triazolyl Azabicyclo[3.1.0]hexanes: a Class of Potent and Selective Dopamine D₃ Receptor Antagonists

Contact Info

Product

Resources

About

1,2,4-Triazolyl Azabicyclo[3.1.0]hexanes: A New Series of Potent and Selective Dopamine D3 Receptor Antagonists

Cited by 55 publications

References 22 publications

Dopamine D3Receptor Antagonist (GSK598809) Potentiates the Hypertensive Effects of Cocaine in Conscious, Freely-Moving Dogs

Dopamine D3Receptor Antagonist (GSK598809) Potentiates the Hypertensive Effects of Cocaine in Conscious, Freely-Moving Dogs

Synthetic chemistry and biological activity of pentafluorosulphanyl (SF5) organic molecules

Triazolyl Azabicyclo[3.1.0]hexanes: a Class of Potent and Selective Dopamine D3 Receptor Antagonists

Contact Info

Product

Resources

About

1,2,4-Triazolyl Azabicyclo[3.1.0]hexanes: A New Series of Potent and Selective Dopamine D₃ Receptor Antagonists

Dopamine D₃Receptor Antagonist (GSK598809) Potentiates the Hypertensive Effects of Cocaine in Conscious, Freely-Moving Dogs

Dopamine D₃Receptor Antagonist (GSK598809) Potentiates the Hypertensive Effects of Cocaine in Conscious, Freely-Moving Dogs

Triazolyl Azabicyclo[3.1.0]hexanes: a Class of Potent and Selective Dopamine D₃ Receptor Antagonists