Excessive activation of the cannabinoid type-1 receptor (CB1) in the brain by synthetic, endogenous or plant-derived
(cannabis sativa) cannabinoids can lead to pathological states, which could be ameliorated by blocking receptor signalling.
However, due to the large number of functions involving the CB1 receptor, direct CB1 antagonist drugs induce side effects
limiting their therapeutic use. During the ERC-StG funded project, we found that a particular endogenous and labile lipid
compound, pregnenolone, acts as an allosteric and signal-specific inhibitor of CB1 receptors in the brain. Thus, stable
pregnenolone-derivative drugs have been produced to exploit the therapeutic potential of allosteric inhibition of CB1 receptor
signalling, which can be used to decrease pathological over-activation of CB1 receptors. One clear pathological state where
over-activation of CB1 receptors plays a key role is schizophrenia and psychotic syndromes. Indeed, cannabis and synthetic
cannabinoids can induce psychotic states and excessive CB1 receptor signalling has been proposed to participate in the
etiopathogenesis of human schizophrenia. Thus, the present project aimed at establishing the innovative and commercial
potential of this new class of drugs, stable derivatives of pregnenolone, as allosteric inhibitors of the CB1 receptor for the
treatment of psychotic syndromes.
The following specific issues were addressed during this project:
1. Technical activities to identify the compounds with the best therapeutic potential.
Pre-clinical studies revealed that pregnenolone and one derivative are very efficient in inhibiting psychotic-like effects of cannabinoid drugs in mice.
Experiments are ongoing presently to extend this proof-of-concept to other cannabinoid-independent models of psychoses.
2. Market studies to determine the potential competitiveness of these compounds.
These studies revealed that the field of psychoses and schizophrenia are requiring new treatments that could cover a large spectrum of symptoms.
The compounds tested so far respond to this requirement, thereby presenting interesting potential competitiveness.
3. Additional industry partnerships for later stages of commercial development.
The partnership with Aelis Farma is advanced and funding are currently sought for proceeding with the development of this class of compounds.
In conclusion, I believe that, by covering these essential steps bridging a scientific idea from basic research to therapeutic applications, the present
project was fully integrated in the spirit of the ERC PoC program and provided medical, economical and
societal information for the development of a new class of drugs potentially able to improve the life of many patients in Europe and in the rest
of the world.
