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While life expectancy increases worldwide, treatment of neurodegenerative diseases such as AD becomes a major task for industrial and academic research. Currently, a treatment of AD is only symptomatical and limited to an early stage of the disease by inhibiting AChE. A cure for AD might even seem far away. A rethinking of other possible targets is therefore necessary. Addressing targets that can influence AD even at later stages might be the key. Even if it is not possible to find a cure for AD, it is of great value for AD patients by providing an effective medication. The suffering of patients and their families might be relieved and remaining years may be spent with less symptoms and restrictions.
It was shown that a combination of hCB2R agonist and BChE inhibitor might exactly be a promising approach to combat AD. In the previous chapters, a first investigation of dual-acting compounds that address both hCB2R and BChE was illustrated (figure 6.1).
A set of over 30 compounds was obtained by applying SARs from BChE inhibitors to a hCB2R
selective agonist developed by AstraZeneca. In a first in vitro evaluation compounds showed
selectivity over hCB1R and AChE. Further investigations could also prove agonism and showed
that unwanted off-target affinity to hMOP receptor could be designed out. The development of
a homology model for hCB2R (based on a novel hCB1R crystal) could further elucidate the
mode of action of the ligand binding. Lastly, first in vivo studies showed a beneficial effect of
selected dual-acting compounds regarding memory and cognition.
Since these first in vivo studies mainly aim for an inhibition of the BChE, it should be the aim
of upcoming projects to proof the relevance of hCB2R agonism in vivo as well. In addition,
pharmacokinetic as well as solubility studies may help to complete the overall picture.
Currently, hybrid-based dual-acting hCB2R agonists and selective BChE inhibitors are under
investigation in our lab. First in vitro evaluations showed improved BChE inhibition and
selectivity over AChE compared to tacrine.78 Future in vitro and in vivo studies will clarify their
usage as drug molecules with regard to hepatotoxicity and blood-brain barrier penetration.
Since the role of hCB2R is not yet completely elucidated, the use of photochromic toolcompounds
becomes an area of interest. These tool-compounds (and their biological effect) can
be triggered upon irradiation with light and thus help to investigate time scales and ligand
binding.
A set of 5-azobenzene benzimidazoles was developed and synthesized. In radioligand binding
studies, affinity towards hCB2R could be increased upon irradiation with UV-light (figure 6.2).
This makes the investigated compounds the first GPCR ligands that can be activated upon
irradiation (not vice versa).
The aim of upcoming research will be the triggering of a certain intrinsic activity by an
“efficacy-switch”. For this purpose, several attempts are currently under investigation: an
introduction of an azobenzene moiety at the 2-position of the benzimidazole core already led to
a slight difference in efficacy upon irradiation with UV light. Another approach going on in our
lab is the development of hCB1R switches based on the selective hCB1R inverse agonist
rimonabant. First in vitro results are not yet available (figure 6.3).