Day 1 :
Karolinska Institute, Sweden
Keynote: Multiple D2 heteroreceptor complexes in the ventral striatum: Relevance for schizophrenia and cocaine use disorder and their treatments
Time : 10:05-10:45
Kjell Fuxe has worked at Karolinska Institute, Sweden since 1960, became Prosektor in 1968 and Professor in 1979. He has been a Professor in the Department of Neuroscience since 2005. He published over 1589 papers. He is a member of Royal Swedish Academy of Sciences and foreign member of Mexican Academy of Sciences and was a member of the Nobel Assembly. He is mainly known for his work on central monoamine neurons, volume transmission and its different forms, receptor-receptor interactions in the CNS and neuropsychopharmacology.
Statement of the Problem: The discovery of allosteric receptor-receptor interactions in GPCR heteroreceptor complexes in the plasma membrane of nerve cells in the CNS gave a new dimension to brain integration, plasticity and neuropsychopharmacology. Aim of this study is to test the hypothesis that different types of D2 heteroreceptor complexes are new targets in the treatment of schizophrenia and cocaine use disorder. D2 receptors in the complexes can also interact with ion channel receptors, receptor tyrosine kinases and/or adapter proteins. Disturbances in the D2 complexes can contribute to schizophrenia development and cocaine use disorder through changes in the balance of the activity of diverse D2 homo-and heteroreceptor complexes of the ventral striatopallidal GABA anti-reward pathway regulating salience.
Methodology & Theoretical Orientation: Proximity ligation assays and biochemical binding techniques were used with behavioral correlates.
Findings: Agonist activation of A2A protomer in the A2A–D2 heteroreceptor complex inhibits D2 Gi/o mediated signaling but increases the D2 β-arrestin2 mediated signaling. Through this allosteric receptor–receptor interaction, the A2A agonist becomes a biased inhibitory modulator of the Gi/o mediated D2 signaling, which may be the main mechanism for its atypical antipsychotic properties. The dopamine (DA) and glutamate hypotheses of schizophrenia come together in the signal integration in D2–NMDAR and A2A–D2–mGluR5 heteroreceptor complexes, especially in the ventral striatum. Cocaine self-administration differentially affected allosteric A2A-D2receptor-receptor interactions in the ventral vs. the dorsal striatum.
Conclusion & Significance: Dysregulation of the meso-limbic DA neurons and their post junctional D2 heteroreceptor targets may be involved in producing the symptoms of schizophrenia. Potential differences in the composition and stoichiometry of the A2A-D2 heteroreceptor complexes, including differential recruitment of sigma 1 receptor, to the ventral vs. dorsal striatum may explain the selective antagonistic A2A-D2 receptor interactions observed after cocaine self-administration in nucleus accumbens explaining the anti-cocaine actions of A2A agonists.
Theodor Bilharz Research Institute, Egypt
Keynote: Potential antischistosomal activity of PDE inhibitors using in vitro Schistosoma mansoni worm killing
Time : 10:45-11:25
TESARO Inc., USA
Time : 11:45-12:25
Zhi-Yi Zhang is a Senior Director at TESARO Inc., an oncology-focused biopharmaceutical company in Waltham, MA, USA. He currently leads a group in Clinical Pharmacology and Drug Disposition supporting the development and regulatory submission of several drug candidates in the late phase of the Tesaro pipeline. Before joining TESARO, he worked at several other biopharmaceutical companies, leading efforts to characterize the absorption, distribution, metabolism, and elimination and drug-drug interactions of small molecule drug leads and candidates at Eisai Inc., and CombinatoRx Inc. He received his Medical degree at Fudan University Medical School, China; MS in Department of Environmental Sciences at Rutgers University, USA, and his PhD in Department of Environmental Health and Toxicology at State University of New York at Albany, USA. He completed his Post-doctoral training in Toxicology Division, Department of Chemistry, Massachusetts Institute of Technology, USA.
Statement of the Problem: Niraparib (ZEJULA™) is a highly selective inhibitor of PARP1&2, approved for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. Here, we present the pharmacokinetic profile of niraparib.
Methodology & Theoretical Orientation: The pharmacokinetics and disposition of niraparib were comprehensively evaluated in preclinical in vitro and in vivo experiments and in three clinical studies aimed at characterizing its absorption, distribution, metabolism, and elimination.
Findings: Niraparib was highly bioavailable (F≈73%) with dose-proportional exposure (30–400 mg) and a consistent accumulation ratio (R≈2) following multiple daily doses in patients. The Vd/F of niraparib was 1220 L in cancer patients, indicating extensive tissue distribution. This was consistent with niraparib’s distribution to rat brain, monkey cerebrospinal fluid, and xenographic tumors, and with its high permeability coefficient (Papp=12–18×106 cm/s) in cultured cells. The primary metabolic pathway via the liver (carboxylesterase-catalyzed amide hydrolysis) led to the formation of an inactive acid metabolite (M1), which is subjected to glucuronidation. Cytochrome P450 enzymes played a negligible role in niraparib metabolism in patients. Niraparib was comparably eliminated via the renal and fecal routes, and exhibited a long terminal half-life (≈2 days), supporting a daily dose regimen. The high recovery of niraparib and its metabolites (86%), accumulating within 21 days in the excreta of patients, suggests minimal long-term body retention.
Conclusion & Significance: Niraparib’s ADME, characterized by high cell permeability and extensive tissue distribution, is consistent with its demonstrated anticancer activity.