University thesis:
Dissertation, Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 2020
Footnote:
Description:
G-protein coupled receptors (GPCRs) represent the largest group of transmembrane receptors with more than 800 members encoded in the human genome. GPCRs mediate cellular responses following stimulation via a pleiotropy of stimuli that include photons, odors, hormones and neurotransmitters. Their abundant expression in various tissues of the human body, link them to major physiological and pathophysiological processes and make them a promising target in drug development with currently about 30% of approved drugs targeting GPCRs. The dopamine receptors D2R and D3R are involved in the pathogenesis of multiple neurological and neuropsychiatric diseases including Parkinson's disease, Schizophrenia, substance addiction and, as recently discovered, neuroinflammation. Especially in the context of drug abuse, the D3R attracts increasing attention and selective antagonists and partial agonists are subject of ongoing clinical trials. Traditionally, class A GPCRs have been considered to signal as isolated entities within the plasma membrane. However, it is now widely accepted that they can also transiently interact with other GPCRs to form homo- and heterodimers. In this context, homodimerization describes an interaction of two identical protomers, while heterodimerization describes the interaction of two distinct receptors. As dimerization can dramatically shift the pharmacology of the involved protomers, an investigation of dimerization properties of the D2R and the D3R provides valuable information on pathogenesis and paves the way towards novel treatment options. The dopaminergic system is anatomically and functionally highly interconnected with the neurotensinergic system and neurotensin elicits antipsychotic effects that are partly due to cross-receptor interactions with dopamine receptors. Based on those findings, our group previously developed a set of bivalent ligands bearing a dopamine receptor pharmacophore and a neurotensin receptor pharmacophore connected to each other by a PEG-based spacer of variable length. ...