RÉSUMÉ
RATIONALE: Sex differences in the dopaminergic response to psychostimulants could have implications for drug abuse risk and other psychopathology involving the dopamine system, but human data are limited and mixed. OBJECTIVES: Here, we sought to investigate sex differences in dopamine release after oral D-amphetamine administration. METHODS: We used [18F]fallypride positron emission tomography (PET) to measure the change in dopamine D2/3 receptor availability (%ΔBPND, an index of dopamine release) between placebo and D-amphetamine sessions in two independent datasets containing a total of 39 females (on either hormonal birth control n = 18, postmenopausal n = 10, or studied in the first 10 days of their menstrual cycle n = 11) and 37 males. RESULTS: Using both a priori anatomical regions of interest based on previous findings and voxelwise analyses, we failed to consistently detect broad sex differences in D-amphetamine-induced dopamine release. Nevertheless, there was limited evidence for greater right ventral striatal dopamine release in young adult males relative to similarly aged females, but this was not consistently observed across samples. Plasma estradiol did not correlate with dopamine release and this measure did not differ in females on and off hormonal birth control. CONCLUSIONS: While our finding in young adults from one dataset of greater %ΔBPND in males is partially consistent with a previously published study on sex differences in D-amphetamine-induced dopamine release, our data do not support the presence of consistent widespread sex differences in this measure of dopamine release.
Sujet(s)
Stimulants du système nerveux central/pharmacologie , Dexamfétamine/pharmacologie , Dopamine/métabolisme , Récepteur D2 de la dopamine/effets des médicaments et des substances chimiques , Récepteur D3 de la dopamine/effets des médicaments et des substances chimiques , Striatum ventral/effets des médicaments et des substances chimiques , Adulte , Sujet âgé , Benzamides , Femelle , Radio-isotopes du fluor , Humains , Mâle , Adulte d'âge moyen , Tomographie par émission de positons , Récepteur D2 de la dopamine/métabolisme , Récepteur D3 de la dopamine/métabolisme , Caractères sexuels , Facteurs sexuels , Striatum ventral/imagerie diagnostique , Striatum ventral/métabolisme , Jeune adulteRÉSUMÉ
Physical activity has been shown to ameliorate dopaminergic degeneration in non-human animal models. However, the effects of regular physical activity on normal age-related changes in dopamine function in humans are unknown. Here we present cross-sectional data from forty-four healthy human subjects between 23 and 80 years old, showing that typical age-related dopamine D2 receptor loss, assessed with PET [18F]fallypride, was significantly reduced in physically active adults compared to less active adults.
Sujet(s)
Vieillissement/métabolisme , Exercice physique/physiologie , Récepteur D2 de la dopamine/physiologie , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Benzamides , Encéphale/imagerie diagnostique , Encéphale/croissance et développement , Encéphale/physiologie , Études transversales , Femelle , Humains , Imagerie par résonance magnétique , Mâle , Adulte d'âge moyen , Tomographie par émission de positons , Radiopharmaceutiques , Récepteur D2 de la dopamine/métabolisme , Récepteur D3 de la dopamine/métabolisme , Jeune adulteRÉSUMÉ
The IAPs are key regulators of the apoptotic pathways and are commonly overexpressed in many cancer cells. IAPs contain one to three BIR domains that are crucial for their inhibitory function. The pro-survival properties of XIAP come from binding of the BIR domains to the pro-apoptotic caspases. The BIR3 domain of XIAP binds and inhibits caspase 9, while the BIR2 domain binds and inhibits the terminal caspases 3 and 7. While XIAP BIR3 inhibitors have previously been reported, they also inhibit cIAP1/2 and promote the release of TNFα, potentially limiting their therapeutic utility. This paper will focus on the optimization of selective XIAP BIR2 inhibitors leading to the discovery of highly potent benzodiazepinone 36 (IC50 = 45 nM), which has high levels of selectivity over XIAP BIR3 and cIAP1 BIR2/3 and shows efficacy in a xenograft pharmacodynamic model monitoring caspase activity while not promoting the release of TNFα in vitro.
Sujet(s)
Composés hétérocycliques/synthèse chimique , Composés hétérocycliques/pharmacologie , Protéines IAP/antagonistes et inhibiteurs , Protéine inhibitrice de l'apoptose liée au chromosome X/antagonistes et inhibiteurs , Alanine/analogues et dérivés , Alanine/synthèse chimique , Alanine/pharmacocinétique , Alanine/pharmacologie , Animaux , Apoptose/effets des médicaments et des substances chimiques , Benzodiazépinones/synthèse chimique , Benzodiazépinones/pharmacocinétique , Benzodiazépinones/pharmacologie , Technique de Western , Caspase-3/métabolisme , Caspase-7/métabolisme , Lignée cellulaire tumorale , Survie cellulaire/effets des médicaments et des substances chimiques , Cristallographie aux rayons X , Femelle , Composés hétérocycliques/pharmacocinétique , Humains , Protéines IAP/composition chimique , Protéines IAP/métabolisme , Souris , Souris nude , Modèles chimiques , Modèles moléculaires , Structure moléculaire , Structure tertiaire des protéines , Ubiquitin-protein ligases , Protéine inhibitrice de l'apoptose liée au chromosome X/composition chimique , Protéine inhibitrice de l'apoptose liée au chromosome X/métabolisme , Tests d'activité antitumorale sur modèle de xénogreffeRÉSUMÉ
A series of pyrimidodiazepines was identified as potent Polo-like kinase 1 (PLK1) inhibitors. The synthesis and SAR are discussed. The lead compound 7 (RO3280) has potent inhibitory activity against PLK1, good selectivity against other kinases, and excellent in vitro cellular potency. It showed strong antitumor activity in xenograft mouse models.
Sujet(s)
Antinéoplasiques/pharmacologie , Azépines/pharmacologie , Protéines du cycle cellulaire/antagonistes et inhibiteurs , Tumeurs expérimentales/traitement médicamenteux , Inhibiteurs de protéines kinases/pharmacologie , Protein-Serine-Threonine Kinases/antagonistes et inhibiteurs , Protéines proto-oncogènes/antagonistes et inhibiteurs , Pyrimidines/pharmacologie , Animaux , Antinéoplasiques/synthèse chimique , Antinéoplasiques/composition chimique , Azépines/synthèse chimique , Azépines/composition chimique , Protéines du cycle cellulaire/métabolisme , Lignée cellulaire tumorale , Prolifération cellulaire/effets des médicaments et des substances chimiques , Relation dose-effet des médicaments , Humains , Souris , Structure moléculaire , Inhibiteurs de protéines kinases/synthèse chimique , Inhibiteurs de protéines kinases/composition chimique , Protein-Serine-Threonine Kinases/métabolisme , Protéines proto-oncogènes/métabolisme , Pyrimidines/synthèse chimique , Pyrimidines/composition chimique , Stéréoisomérie , Relation structure-activité ,RÉSUMÉ
A novel series of quinolinyl-methylene-thiazolinones has been identified as potent and selective cyclin-dependent kinase 1 (CDK1) inhibitors. Their synthesis and structure activity relationships (SAR) are described. Representative compounds from this class reversibly inhibit CDK1 activity in vitro, and block cell cycle progression in human tumor cell lines, suggesting a potential use as antitumor agents.