Jonas Skovgaard-Petersen

August 2010 – present
PhD student, Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen.

August 2006 – July 2009
M.Sc. Human Biology, Faculty of Health Sciences, University of Copenhagen

August 2001 – June 2005
B.Sc. Biology, Faculty of Science, University of Copenhagen

Radioactive Isotopes and Ionizing Radiation, University of Copenhagen (2008)
Laboratory Animal Science (FELASA Cat. C), University of Copenhagen (2007)

Project title
Molecular pharmacology of GABA transporters – probing for subtype selectivity

Background
g-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian brain. Normal GABAergic neurotransmission is critically dependent on the termination of signaling by removal of GABA from the synaptic cleft and re-uptake into synaptic processes by GABA transporters (GATs).  At present, four different subtypes of GATs exist (GAT-1, BGT-1, GAT-2, GAT-3), each with a unique subcellular distribution among neurons and glial cells. Inhibition of specific GAT subtypes enhances GABAergic transmission and poses a novel pharmacological strategy for treating disorders associated with GABAergic hypoactivity such as epilepsy, anxiety and sleep disorders. At present, only one drug, Gabitril^Ò (Tiagabine), a potent and selective inhibitor of GAT-1, is used for treatment of epilepsy. However, the physiological function and therapeutic potential of the non-GAT-1 subtypes remains unclear, as no selective potent drugs against these transporters are commercially available. The overall aim of this project is to gain molecular and pharmacological insight into GAT subtypes by identifying and characterizing subtype-selective compounds.

Objective
The objective of the present project is twofold. 1) To characterize the molecular determinants, binding and mechanism of action of BC-TK-08, a novel in-house-developed selective inhibitor of BGT-1. (2) To identify novel GAT inhibitors of natural origin and investigate their pharmacological effects both in vitro and in vivo.

Approach
The subtype selectivity and inhibitory effects of synthesized and natural compounds will be evaluated in [³H]GABA uptake assays in which cells have been transiently transfected with one of the human GATs. In order to determine the molecular binding properties of BC-TK-08 and related analogues at BGT-1, we will generate functional chimeras between BGT-1 and GAT-3 and test these in both uptake assay and the FLIPR membrane potential (FMP) assay. To further elucidate the binding region and identify the amino acids involved, we will analyze individual point mutations using an epitope-tagged variant of the BGT-1 transporter. Finally, anticonvulsive effects of selected drugs will be tested in vivo in various mouse seizure models.

Main advisor
Petrine Wellendorph, PhD, Assoc. Professor, Department of Medicinal Chemistry

Co-advisors
Jerzy Jaroszewski, PhD, Professor, Department of Medicinal Chemistry
Karsten Kirkegaard Madsen, PhD, Post doc, Department of Pharmacology and Pharmacotherapy