APPROACH

 
A NOVEL MECHANISM TO MODULATE THE ENDOCANNABINOID SYSTEM

The ECS is composed of two major G-protein couple receptors named cannabinoid receptor type-1 (CB1) and type-2 (CB2), a class of endogenous signaling lipids (endocannabinoids) and a series of enzymes involved in their biosynthesis and degradation.

The two most abundant and well-studied endocannabinoids are anandamide (AEA) and 2-arachidonoyl glycerol (2-AG). At the synaptic level, upon the arrival of an action potential, neurotransmitters are released from presynaptic neurons into the synaptic cleft.

Increase of intracellular Ca2+ concentration in the postsynaptic neurons activates the biosynthetic enzymes for AEA and 2-AG, which are released in the synaptic cleft. Endocannabinoids activate CB1 receptors expressed on pre-synaptic neurons blocking the release of further neurotransmitters (negative feedback, retrograde signaling). Finally, endocannabinoids are transported intracellularly where they are degraded by specific enzymes.

 

Although data from independent laboratories have clearly suggested the existence of an endocannabinoid membrane transport mechanism (reviewed in Nicolussi & Gertsch, 2015), this has remained elusive for many years.

Thanks to the prolonged support of NCCR TransCure and other founding agencies, recently the research group of Prof. Jürg Gertsch at the University of Bern was successful to identify the molecular entities responsible for endocannabinoid transport across cell membranes (not yet published) and first-in-class selective endocannabinoid reuptake inhibitors (SERIs).

First generation SERIs have been instrumental to uncover a new pharmacological modulation of the endocannabinoid system resulting from the inhibition of endocannabinoid cell reuptake (Chicca et al., PNAS 2017Reynoso-Moreno et al., 2018).

SERIs’ mechanism of action enables restoration of the full spectrum of endocannabinoid biological activities.

 
THE POTENTIAL FOR TREATMENT

Preclinical and clinical evidence links endocannabinoid deficiency with different diseases related to CNS and peripheral organs. The strongest evidence correlates endocannabinoid deficiency with anxiety, stress and mood-related disorders and inflammatory diseases.

One of the major reasons of endocannabinoid deficiency is the higher expression of the degrading enzymes in pathophysiological conditions. SERIs exert the maximal pharmacological effect during disease conditions (time-limited) and in the tissue or brain region primarily involved in the disease (space-specific).

The competitive, non-covalent and reversible mechanism of action of SERIs exerts pro-homeostatic effects on the endocannabinoid system and limits the risk of an excessive, prolonged and ubiquitous accumulation of endocannabinoids.

The endocannabinoid system is a key neuromodulator system in the CNS and it is involved in regulating neurotransmitter release of major neuronal circuits. Modulation of the endocannabinoid system can enable restoration of normal functioning of the brain by rebalancing dysregulated neurotransmission in CNS disorders.

SERIs’ mechanism of action can translate into a better safety profile for short and long term use and an improved therapeutic control of the symptoms associated to anxiety, mood and stress-related disorders.

SERIs represent a novel therapeutic approach to treat CNS disorders characterized by endocannabinoid deficiency through a fine-tuned modulation of the endocannabinoid system.

 
SERIs DESIGN AND DEVELOPMENT

The design and development of second generation SERIs started in 2012 from an in silico ligand polypharmacophore screening of >12 million compounds, followed by an effective medicinal chemistry programme (in collaboration with a CRO).

In total, more than 800 purchasable and newly synthesized compounds were tested with the identification of three lead compounds in 2017. An additional characterization of the safety and efficacy profile of these three lead compounds led to the identification of SYT-510 as our preclinical drug candidate with two possible follow up/back up compounds.

An innovative screening platform based upon the exclusive access to the mechanism of endocannabinoid cell reuptake will enable Synendos to develop new generation of inhibitors (target-based) and new classes of modulators with unique pharmacological features in the endocannabinoid system.

 

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