From heterodimerization to new synthetic opioids: there is MORe than meets the eye in Mu Opioid Receptor signaling

Lakshmi Vasudevan
Faculteit Farmaceutische Wetenschappen
Vakgroep Bioanalyse
Master of Science in Biochemistry, Lokmanya Tilak Municipal Medical College, University of Mumbai, India, 2008-2010 Bachelor of Science in Biochemistry, Ramnarain Ruia College, University of Mumbai, India, 2005-2008 Advanced Diploma in Food Science & Quality Control, Ramnarain Ruia College, India, 2005-2008
Academische graad
Doctor in de farmaceutische wetenschappen
Taal proefschrift
Vertaling titel
Van heterodimerisatie tot nieuwe synthetische opioïden: nieuwe aspecten van signalisatie via de mu opioïde receptor
Prof. dr., Christophe Stove, UGent-Bioanalyse - Prof. dr., Deepak K. Saini, Indian Institute of Science
Prof. dr., Serge Van Calenbergh, UGent-Geneesmiddelenleer - Prof. dr., Dieter Deforce, UGent-Geneesmiddelenleer - Prof. dr., Sarah Gerlo, UGent-VIB - Dr., Andy Chevigné, Luxembourg Institute of Health - Dr., Christel Menet, Confo Therapeutics - Dr., Dasiel Borroto Escuela, Karolinska Institutet

Korte beschrijving

In this thesis, Mu Opioid Receptor (MOR) was studied from two different angles, giving rise to a thesis encompassing two distinct, yet related, parts. Part 1 mainly focussed on the interaction of MOR with Dopamine D2 receptor, which was studied using biochemical-biophysical techniques. Furthermore, live cell imaging revealed that D2LR, when co-expressed with MOR, slowed down internalization of MOR, following activation with the MOR agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO). Central in Part 2 are novel synthetic opioids (NSO). This is the deadliest class of new psychoactive substances (NPS), which are synthetic derivatives of existing psychoactive drugs with a slightly tweaked structure to circumvent detection and legislation. Opioids are best known for their analgesic effects but are also associated with unwanted side effects. On the signaling level downstream from MOR, analgesia has been reported to be mainly mediated through the G protein pathway, while undesirable effects have been linked to the β-arrestin pathway. As little is known about the potential ‘bias’ (i.e. the preferential activation of one pathway over the other) of these NSO, we developed and applied a novel, stable, robust bio-assay platform. This was used to study the potential of 21 synthetic opioids to cause recruitment of mini-Gi (GTPase domain of Gαi subunit), or β-arrestin 2, to activated MOR, using split nanoluciferase technology. Although none of the tested NSO was significantly biased towards any of the two pathways, remarks about some tendencies for some NSO were made cautiously, which could help to gain some preliminary insights and may be useful for future compound design. Another bio-assay based on the recruitment to MOR of a Gi protein mimetic, derived from camelids, nanobody 39, was also developed and compared to the MOR-mini-Gi assay. Both bio-assays yielded similar potencies but distinct raw activation profiles for a selected set of NSO.


Donderdag 24 oktober 2019, 18:00
Auditorium 2, Ottergemsesteenweg 460, 9000 Gent