ABSTRACT
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.
Subject(s)
Central Nervous System Stimulants/pharmacology , Dextroamphetamine/pharmacology , Dopamine/metabolism , Receptors, Dopamine D2/drug effects , Receptors, Dopamine D3/drug effects , Ventral Striatum/drug effects , Adult , Aged , Benzamides , Female , Fluorine Radioisotopes , Humans , Male , Middle Aged , Positron-Emission Tomography , Receptors, Dopamine D2/metabolism , Receptors, Dopamine D3/metabolism , Sex Characteristics , Sex Factors , Ventral Striatum/diagnostic imaging , Ventral Striatum/metabolism , Young AdultABSTRACT
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.
Subject(s)
Aging/metabolism , Exercise/physiology , Receptors, Dopamine D2/physiology , Adult , Aged , Aged, 80 and over , Benzamides , Brain/diagnostic imaging , Brain/growth & development , Brain/physiology , Cross-Sectional Studies , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Positron-Emission Tomography , Radiopharmaceuticals , Receptors, Dopamine D2/metabolism , Receptors, Dopamine D3/metabolism , Young AdultABSTRACT
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.
Subject(s)
Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/pharmacology , Inhibitor of Apoptosis Proteins/antagonists & inhibitors , X-Linked Inhibitor of Apoptosis Protein/antagonists & inhibitors , Alanine/analogs & derivatives , Alanine/chemical synthesis , Alanine/pharmacokinetics , Alanine/pharmacology , Animals , Apoptosis/drug effects , Benzodiazepinones/chemical synthesis , Benzodiazepinones/pharmacokinetics , Benzodiazepinones/pharmacology , Blotting, Western , Caspase 3/metabolism , Caspase 7/metabolism , Cell Line, Tumor , Cell Survival/drug effects , Crystallography, X-Ray , Female , Heterocyclic Compounds/pharmacokinetics , Humans , Inhibitor of Apoptosis Proteins/chemistry , Inhibitor of Apoptosis Proteins/metabolism , Mice , Mice, Nude , Models, Chemical , Models, Molecular , Molecular Structure , Protein Structure, Tertiary , Ubiquitin-Protein Ligases , X-Linked Inhibitor of Apoptosis Protein/chemistry , X-Linked Inhibitor of Apoptosis Protein/metabolism , Xenograft Model Antitumor AssaysABSTRACT
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.
Subject(s)
Antineoplastic Agents/pharmacology , Azepines/pharmacology , Cell Cycle Proteins/antagonists & inhibitors , Neoplasms, Experimental/drug therapy , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , Pyrimidines/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Azepines/chemical synthesis , Azepines/chemistry , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Humans , Mice , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins/metabolism , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Stereoisomerism , Structure-Activity Relationship , Polo-Like Kinase 1ABSTRACT
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.
