Unmet needs in hyperkinetic movement disorders (HMDs) within neuropsychiatric conditions include better treatments for HMDs in complex disorders like Huntington's disease (HD), Tourette syndrome and psychiatric comorbidities like tardive dyskinesia. The symptomatology of HD comprises chorea, a disabling movement disorder, neuropsychiatric disturbances and cognitive decline. VMAT2 inhibitors like tetrabenazine and its derivatives, as well as antipsychotics, are used for the treatment of HMDs but they may worsen motor function or the underlying neuropsychiatric symptoms. Specifically targeted therapies improving management of motor and non-motor symptoms with a safety profile suited for continued chronic treatment are needed. We describe here the novel mechanism of action of SOM3355, a CNS-permeant selective beta 1-blocker (bevantolol) found to have additional VMAT2 and VMAT1 modulation activity. SOM3355 is a clinical drug candidate for the treatment of HD that has shown positive clinical effects in the motor-behavioral/psychiatric-cognitive symptom triad characteristic of the disease. In vitro and in vivo studies were conducted to evaluate SOM3355's inhibitory activity at VMAT1, VMAT2 and CNS targets. Functional uptake and radioligand binding assays were performed in rat vesicles and human recombinant systems. SOM3355 inhibited VMAT2-mediated dopamine uptake comparably to tetrabenazine but displayed markedly lower affinity for the alpha-dihydrotetrabenazine binding site, suggesting a distinct interaction mode. Unlike tetrabenazine, SOM3355 potently inhibited VMAT1, a vesicular monoamine transporter present in different brain areas and implicated in neuropsychiatric regulation. Additionally, SOM3355 exhibited negligible off-target CNS binding, consistent with the favorable CNS safety profile observed in clinical trials. By combining synergistic beta 1-adrenergic antagonism, VMAT2-mediated dopamine modulation, and VMAT1 inhibition, SOM3355 may address monoamine neurotransmitter imbalances within basal ganglia and cortical circuits involved in motor and neuropsychiatric manifestations of HD. In summary, the translational profile of SOM3355, aligned with its clinical evaluation to date, supports its positioning as a potential novel therapeutic alternative for the treatment of HMDs and neuropsychiatric conditions like HD, tardive dyskinesia and Tourette Syndrome.
SOM3355: a unique pharmacological profile combining VMAT1 inhibition, VMAT2-mediated dopamine modulation, and β1-adrenergic antagonism for the treatment of movement and neuropsychiatric disorders
Turilli-Ghisolfi E. S.Primo
;
2026-01-01
Abstract
Unmet needs in hyperkinetic movement disorders (HMDs) within neuropsychiatric conditions include better treatments for HMDs in complex disorders like Huntington's disease (HD), Tourette syndrome and psychiatric comorbidities like tardive dyskinesia. The symptomatology of HD comprises chorea, a disabling movement disorder, neuropsychiatric disturbances and cognitive decline. VMAT2 inhibitors like tetrabenazine and its derivatives, as well as antipsychotics, are used for the treatment of HMDs but they may worsen motor function or the underlying neuropsychiatric symptoms. Specifically targeted therapies improving management of motor and non-motor symptoms with a safety profile suited for continued chronic treatment are needed. We describe here the novel mechanism of action of SOM3355, a CNS-permeant selective beta 1-blocker (bevantolol) found to have additional VMAT2 and VMAT1 modulation activity. SOM3355 is a clinical drug candidate for the treatment of HD that has shown positive clinical effects in the motor-behavioral/psychiatric-cognitive symptom triad characteristic of the disease. In vitro and in vivo studies were conducted to evaluate SOM3355's inhibitory activity at VMAT1, VMAT2 and CNS targets. Functional uptake and radioligand binding assays were performed in rat vesicles and human recombinant systems. SOM3355 inhibited VMAT2-mediated dopamine uptake comparably to tetrabenazine but displayed markedly lower affinity for the alpha-dihydrotetrabenazine binding site, suggesting a distinct interaction mode. Unlike tetrabenazine, SOM3355 potently inhibited VMAT1, a vesicular monoamine transporter present in different brain areas and implicated in neuropsychiatric regulation. Additionally, SOM3355 exhibited negligible off-target CNS binding, consistent with the favorable CNS safety profile observed in clinical trials. By combining synergistic beta 1-adrenergic antagonism, VMAT2-mediated dopamine modulation, and VMAT1 inhibition, SOM3355 may address monoamine neurotransmitter imbalances within basal ganglia and cortical circuits involved in motor and neuropsychiatric manifestations of HD. In summary, the translational profile of SOM3355, aligned with its clinical evaluation to date, supports its positioning as a potential novel therapeutic alternative for the treatment of HMDs and neuropsychiatric conditions like HD, tardive dyskinesia and Tourette Syndrome.
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