The project investigates brain mechanisms involving g-hydroxybutyric acid (GHB). We recently discovered that GHB binds to the protein Ca2+/calmodulin-dependent protein kinase II alpha (CaMKIIa), a central brain enzyme.
The aim of the project is to understand molecular interactions of our developed GHB related compounds at CaMKIIa, and to utilize this for developing new and better medicines for brain diseases such as cerebral ischemia and narcolepsy.
GHB is a naturally occurring brain substance. GHB is a clinically used drug in the sleep disorder narcolepsy, and an analogue of GHB has shown therapeutic promise in ameliorating stroke effects in mice. Currently, there is no effective medicine for stroke. Through pioneering work, we have found that analogues of g-hydroxybutyrate (GHB) bind selectively to the CaMKIIa – an enzyme responsible for higher brain function in mammals and involved in many brain diseases.
Expected outcomes and perspectives
The research will reveal the significance of GHB related compounds at CaMKIIa as the first small molecules interacting selectively with this important drug target. Our research may therefore outline new therapeutic options for other diseases involving CaMKII.
The project uses methods within medicinal chemistry, biochemistry, structural biology, molecular pharmacology, in vitro pharmacology and in vivo animal models through a range of internal and external collaborators
Bente Frølund, UCPH, MolNeuroPro cluster ,
Andrew N. Clarkson, University of Otago, New Zealand
Geeske van Woerden, Erasmus Medical University, Rotterdam, Netherlands
John Kuriyan, University of California Berkeley, US
Birgitte Kornum, Department of Neuroscience, University of Copenhagen
- Leurs U, Klein AB, McSpadden ED, Griem-Krey N, Solbak SMØ, Houlton J, Villumsen IS, Vogensen SB, Hamborg, L, Gauger SJ, Palmelund LB, Larsen ASG, Shehata MA, Kelstrup CD, Olsen, JV, Bach A, Burnie RO, Kerr S, Gowing EK, Teurlings SMW, Chi CC, Gee CL, Frølund B, Kornum BR, van Woerden GM, Clausen RP, Kuriyan J, Clarkson AN & Wellendorph P. GHB confers neuroprotection by stabilizing the CaMKIIa hub domain. Published on BioRxiv Sep 28, 2020
- Krall J, Bavo F, Falk-Petersen CB, Jensen CH, Nielsen JO, Tian Y, Anglani V, Kongstad K, Piilgaard L, Nielsen B, Gloriam DE, Kehler J, Jensen AA, Harpsøe K, Wellendorph P & Frølund B. Discovery of 2-(imidazo[1,2-b]pyridazin-2-yl)acetic acid as a new class of ligands selective for the γ-hydroxybutyric acid (GHB) high-affinity binding sites. J. Med. Chem. 62: 2798-2813 (2019).
- Krall J, Jensen CH, Bavo F, Falk-Petersen CB, …, Gloriam DE, Clausen RP, Harpsøe K, Wellendorph P & Frølund B. Molecular hybridization of potent and selective γ-hydroxybutyric acid (GHB) ligands: Design, synthesis, binding studies, and molecular modeling of novel 3-hydroxycyclopent-1-enecarboxylic acid (HOCPCA) and trans-γ-hydroxycrotonic acid (T-HCA) analogs. J. Med. Chem. 60: 9022-9039 (2017).
- Klein AB, Bay T, Villumsen IS, Falk-Petersen CB, Marek A, Frølund B, Clausen RP, Hansen HD, Knudsen GM & Wellendorph P. Autoradiographic imaging and quantification of the high-affinity GHB binding sites in rodent brain using 3H-HOCPCA. Neurochem. Int. 100: 138-145 (2016).
- Wellendorph P, Høg S, Greenwood JR, De Lichtenberg A, Nielsen B, Frølund B, Brehm L, Clausen RP & Bräuner-Osborne H. Novel cyclic g-hydroxybutyrate (GHB) analogues with high affinity and stereoselectivity of binding to GHB sites in rat brain. J. Pharmacol. Exp. Ther. 315: 346-351 (2005).
The project is funded through a Lundbeck Foundation thematic grant (2019-2024)