1,2,4-Triazol-3-yl-thiopropyl-tetrahydrobenzazepines:  A Series of Potent and Selective Dopamine D<sub>3</sub> Receptor Antagonists

Micheli, Fabrizio; Bonanomi, Giorgio; Blaney, Frank E.; Braggio, Simone; Capelli, Anna Maria; Checchia, Anna; Curcuruto, Ornella; Damiani, Federica; Fabio, Romano Di; Donati, Daniele; Gentile, Gabriella; Gribble, Andy; Hamprecht, Dieter; Tedesco, Giovanna; Terreni, Silvia; Tarsi, Luca; Lightfoot, Andrew P.; Stemp, Geoff; Macdonald, Gregor; Smith, Alex; Pecoraro, Michela; Petrone, Marcella; Perini, Ornella; Piner, Jacqui; Rossi, Tino; Worby, Angela; Pilla, Maria; Valerio, Enzo; Griffante, Cristiana; Mugnaini, Manolo; Wood, Martyn; Scott, Claire M.; Andreoli, Michela; Lacroix, Laurent; Schwarz, Adam J.; Gozzi, Alessandro; Bifone, Angelo; Ashby, Charles R.; Hagan, Jim J.; Heidbreder, Christian

doi:10.1021/jm0705612

Cited by 82 publications

(92 citation statements)

References 37 publications

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“…These molecules are a series of 1,2,4-triazol-3-yl-thiopropyl-tetrapydrobenzazepines, which are potent and selective dopamine D 3 receptor antagonists. It has been reported that D 3 receptor antagonists tend to exhibit hERG toxicity [53] . The top 11-20 of the good features are from sertindole analogues, Wombat-PK database molecules and h5-HT 2A receptor antagonists, which are mostly strong hERG blockers [48,54,55] .…”

Section: Molecular Features Important For Hergmentioning

confidence: 99%

Novel Bayesian classification models for predicting compounds blocking hERG potassium channels

Lü

Yin

et al. 2014

Acta Pharmacol Sin

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Aim: A large number of drug-induced long QT syndromes are ascribed to blockage of hERG potassium channels. The aim of this study was to construct novel computational models to predict compounds blocking hERG channels. Methods: Doddareddy's hERG blockage data containing 2644 compounds were used, which divided into training (2389) and test (255) sets. Laplacian-corrected Bayesian classification models were constructed using Discovery Studio. The models were internally validated with the training set of compounds, and then applied to the test set for validation. Doddareddy's experimentally validated dataset with 60 compounds was used for external test set validation. Results: A Bayesian classification model considering the effects of four molecular properties (M w , PPSA, ALogP and pK a _basic) as well as extended-connectivity fingerprints (ECFP_14) exhibited a global accuracy (91%), parameter sensitivity (90%) and specificity (92%) in the test set validation, and a global accuracy (58%), parameter sensitivity (61%) and specificity (57%) in the external test set validation. Conclusion: The novel model is better than those in the literatures for predicting compounds blocking hERG channels, and can be used for large-scale prediction.

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Section: Molecular Features Important For Hergmentioning

confidence: 99%

Novel Bayesian classification models for predicting compounds blocking hERG potassium channels

Lü

Yin

et al. 2014

Acta Pharmacol Sin

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“…The dose of D-amphetamine was chosen based on previous in vivo studies Gozzi et al, 2011). The dose ensures robust brain activation, does not produce 'ceiling' rCBV responses (Micheli et al, 2007), and elicits transient MABP responses that are homeostatically compensated under halothane anesthesia (Gozzi et al, 2007;Zaharchuk et al, 1999).…”

Section: Magnetic Resonance Imagingmentioning

confidence: 99%

Neuroimaging Evidence of Altered Fronto-Cortical and Striatal Function after Prolonged Cocaine Self-Administration in the Rat

Gozzi

Tessari

Dacome

et al. 2011

Neuropsychopharmacol

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Cocaine addiction is often modeled in experimental paradigms where rodents learn to self-administer (SA) the drug. However, the extent to which these models replicate the functional alterations observed in clinical neuroimaging studies of cocaine addiction remains unknown. We used magnetic resonance imaging (MRI) to assess basal and evoked brain function in rats subjected to a prolonged, extended-access cocaine SA scheme. Specifically, we measured basal cerebral blood volume (bCBV), an established correlate of basal metabolism, and assessed the reactivity of the dopaminergic system by mapping the pharmacological MRI (phMRI) response evoked by the dopamine-releaser amphetamine. Cocaine-exposed subjects exhibited reduced bCBV in fronto-cortical areas, nucleus accumbens, ventral hippocampus, and thalamus. The cocaine group also showed an attenuated functional response to amphetamine in ventrostriatal areas, an effect that was significantly correlated with total cocaine intake. An inverse relationship between bCBV in the reticular thalamus and the frontal response elicited by amphetamine was found in control subjects but not in the cocaine group, suggesting that the inhibitory interplay within this attentional circuit may be compromised by the drug. Importantly, histopathological analysis did not reveal significant alterations of the microvascular bed in the brain of cocaine-exposed subjects, suggesting that the imaging findings cannot be merely ascribed to cocaine-induced vascular damage. These results document that chronic, extended-access cocaine SA in the rat produces focal fronto-cortical and striatal alterations that serve as plausible neurobiological substrate for the behavioral expression of compulsive drug intake in laboratory animals.

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“…The dopamine D 3 receptor (DRD3) is located predominantly in the limbic system, and particularly in the nucleus accumbens, which plays a critical role in alcohol reward and reinforcement behaviors [6,7]. The results of several preclinical animal studies of substance and alcohol addiction support the efficacy of selective DRD3 antagonists such as SB-277011A, SB-414796, compound 35, and NGB2904 [8,9,10,11,12,13,14]. …”

Section: Introductionmentioning

confidence: 99%

DRD3 Gene rs6280 Polymorphism May Be Associated with Alcohol Dependence Overall and with Lesch Type I Alcohol Dependence in Koreans

Kang

Lee

Lee³

et al. 2014

Neuropsychobiology

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Background: Several polymorphisms of the dopamine D₃ receptor (DRD3) gene are reported to be involved in the susceptibility to alcoholism. Although the DRD3 rs6280 (Ser9Gly) polymorphism plays an important role in various psychiatric disorders, findings regarding the association between this single-nucleotide polymorphism (SNP) and alcohol dependence (AD) have been inconsistent. Therefore, the present study investigated the association between the DRD3 gene rs6280 polymorphism with AD and Lesch type I AD in Korean subjects. Methods: The DRD3 rs6280 SNP was genotyped in a case-control sample comprising 245 AD patients and 130 healthy controls (HCs). Alcohol Use Disorders Identification Test (AUDIT) scores were also compared relative to genotype in all of the participants. Results: This SNP was significantly associated with both AD overall (χ² = 10.09 and p = 0.001, and χ² = 10.60 and p = 0.005, for the recessive and additive models, respectively) and with Lesch type I AD (χ² = 11.70 and p = 0.001, and χ² = 11.70 and p = 0.003, for the recessive and additive models, respectively). The allele frequency differed significantly (χ² = 8.45, p = 0.004) between Lesch type I AD and HC subjects. The AUDIT total (F = 6.56, p = 0.011), hazardous alcohol use (F = 7.12, p = 0.008), dependence symptoms (F = 5.10, p = 0.025), and harmful alcohol use (F = 4.83, p = 0.029) scores were significantly higher in those who did not possess the S allele (genotype GG) than in those who did (genotypes SS ± SG). Conclusions: The findings of this study suggest that the DRD3 rs6280 polymorphism is associated with the development of both AD overall and Lesch type I AD in Koreans.

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1,2,4-Triazol-3-yl-thiopropyl-tetrahydrobenzazepines: A Series of Potent and Selective Dopamine D₃ Receptor Antagonists

Cited by 82 publications

References 37 publications

Novel Bayesian classification models for predicting compounds blocking hERG potassium channels

Novel Bayesian classification models for predicting compounds blocking hERG potassium channels

Neuroimaging Evidence of Altered Fronto-Cortical and Striatal Function after Prolonged Cocaine Self-Administration in the Rat

DRD3 Gene rs6280 Polymorphism May Be Associated with Alcohol Dependence Overall and with Lesch Type I Alcohol Dependence in Koreans

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1,2,4-Triazol-3-yl-thiopropyl-tetrahydrobenzazepines: A Series of Potent and Selective Dopamine D3 Receptor Antagonists

Cited by 82 publications

References 37 publications

Novel Bayesian classification models for predicting compounds blocking hERG potassium channels

Novel Bayesian classification models for predicting compounds blocking hERG potassium channels

Neuroimaging Evidence of Altered Fronto-Cortical and Striatal Function after Prolonged Cocaine Self-Administration in the Rat

DRD3 Gene rs6280 Polymorphism May Be Associated with Alcohol Dependence Overall and with Lesch Type I Alcohol Dependence in Koreans

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1,2,4-Triazol-3-yl-thiopropyl-tetrahydrobenzazepines: A Series of Potent and Selective Dopamine D₃ Receptor Antagonists