Science
Leading Innovation in Endocannabinoid System Therapeutics
Building on the distinct knowledge and experience of our team, Synendos is developing and advancing a proprietary pipeline of endocannabinoid system (ECS) modulators to deliver ground-breaking treatment to patients living with mental conditions.
The ECS is a master regulator of brain function and a clinically validated pillar in neuroscience with demonstrated therapeutic benefits in major CNS disease areas. Selective Endocannabinoid Reuptake Inhibitors (SERIs) are first-in-class small molecules with a new mode of action specifically designed to holistically rebalance brain function across multiple neurological and psychiatric disorders.
SERIs were developed following over a decade of academic research to harness the full potential of the ECS in a physiological manner without overstimulation.
Our mission is to develop and deliver first-in-class, mechanism-based therapies that address the underlying neurobiology of disorders such as Post-Traumatic Stress Disorder (PTSD).
World-Leading Expertise
The Endocannabinoid System
Synendos is pursuing a newly identified drug target within the endocannabinoid system (ECS) to restore natural brain function.
The ECS is a lipid-signaling system widely expressed in the central nervous system (CNS) that acts as a master regulator of brain function, with a primary role in modulating anxiety, mood, stress, memory, sleep, neuroinflammation and pain to name but a few. The ECS is composed of several key elements, as schematically depicted below. These include two major receptors named cannabinoid receptor type-1 (CB1) and type-2 (CB2), a class of endogenous signaling lipids known as endocannabinoids and a set 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, the arrival of an action potential triggers the release of neurotransmitters from presynaptic neurons into the synaptic cleft. These neurotransmitters travel across the cleft and activate specific ionotropic and metabotropic receptors on the postsynaptic neurons, allowing neurotransmission to continue. In parallel, other biochemical pathways are activated in the postsynaptic neurons to drive the biosynthesis of AEA and 2-AG, which are then released into the synaptic cleft.
Endocannabinoids travel across the synaptic cleft in the opposite direction of neurotransmitters and activate CB1 receptors located on pre-synaptic neurons. Activation of CB1 receptor signaling inhibits further neurotransmitter release, functioning as a critical negative feedback mechanism to control neurotransmission (retrograde signaling). Endocannabinoid signaling is terminated by cell reuptake followed by intracellular degradation mediated by specific enzymes.
Although data from independent laboratories have long suggested the existence of a membrane transport mechanism for endocannabinoids (reviewed in Nicolussi & Gertsch, 2015), its molecular identity remained elusive for many years. Following several years of dedicated academic research, the laboratory of Prof. Jürg Gertsch at the University of Bern successfully identified the molecular entity responsible for endocannabinoid transport across cell membranes (scientific publication in preparation).
SERIs represent the first class of potent and selective inhibitors targeting the endocannabinoid transporter to enable physiological enhancement of endocannabinoid levels, without overstimulation, to unlock the full therapeutic potential of the ECS.
The Potential for Treatment
Preclinical and clinical evidence demonstrates that dysregulation of the ECS is associated with a range of diseases affecting both the CNS and peripheral organs. One of the reasons for this dysfunction is an increased expression of endocannabinoid degrading enzymes under pathophysiological conditions, leading to reduced endocannabinoid levels. SERIs are designed to exert their maximal therapeutic effect specifically under disease conditions and within the tissues or brain regions most directly involved, enabling targeted modulation of the ECS.
The competitive, non-covalent and reversible mechanism of action of SERIs results in a gentle and localized enhancement of the endocannabinoid levels within the physiological range without an excessive, prolonged and ubiquitous accumulation of these lipids. This targeted modulation is sufficient to unlock the full potential of the ECS while avoiding overstimulation, representing a key potential point of differentiation from other approaches to modulating the ECS.
First generation SERI tool compounds were instrumental in uncovering a new pharmacological modulation of the ECS through inhibition of endocannabinoid cell reuptake (Chicca et al., PNAS 2017; Reynoso-Moreno et al., 2018; Reynoso-Moreno et al., 2021; Straiker et al. 2020).
Second generation drug-like SERIs (the SYT-series) are currently under clinical development for multiple neuropsychiatric disorders.
Restoring the Balance
The ECS is a key neuromodulatory system that acts upstream of the major neuronal circuits to maintain coordinated function across the interconnected brain network. Its role can be compared to an orchestra conductor, whose primary responsibility is to harmonize and synchronize individual instrument's performance to deliver a flawless melody. Just as a conductor does not directly produce music by playing an instrument, the ECS does not directly drive neurotransmission, as it does not elicit an action potential itself.
The ECS represents a clinically validated therapeutic target for restoring brain function across multiple neuropsychiatric disorders.
The self-limiting, competitive, and reversible mechanism of action of SERIs offers a differentiated approach to harnessing the full potential of the ECS in a physiological manner without overstimulation. This new therapeutic modality is designed to holistically rebalance brain function, with the potential to treat a broad spectrum of symptoms with sustained efficacy in large patient populations. Furthermore, SERIs aim to address a key unmet need, that of chronic tolerability, allowing more patients to stay on treatment and achieve meaningful, durable improvements in quality of life.