{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T02:13:24Z","timestamp":1790648004626,"version":"4.1.0"},"reference-count":64,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T00:00:00Z","timestamp":1779148800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>\n                    Unmet needs in hyperkinetic movement disorders (HMDs) within neuropsychiatric conditions include better treatments for HMDs in complex disorders like Huntington\u2019s 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 \u03b2\n                    <jats:sub>1<\/jats:sub>\n                    -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.\n                    <jats:italic>In vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    studies were conducted to evaluate SOM3355\u2019s 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 \u03b1-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 \u03b2\n                    <jats:sub>1<\/jats:sub>\n                    -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.\n                  <\/jats:p>","DOI":"10.3389\/fphar.2026.1824708","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T05:39:12Z","timestamp":1779169152000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["SOM3355: a unique pharmacological profile combining VMAT1 inhibition, VMAT2-mediated dopamine modulation, and \u03b21-adrenergic antagonism for the treatment of movement and neuropsychiatric disorders"],"prefix":"10.3389","volume":"17","author":[{"given":"Emily S.","family":"Turilli-Ghisolfi","sequence":"first","affiliation":[{"name":"SOM Innovation Biotech SA","place":["Barcelona, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svein Isungset","family":"St\u00f8ve","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, University of Bergen","place":["Bergen, Norway"]},{"name":"Department of Neurology, Neuro-SysMed, Haukeland University Hospital","place":["Bergen, Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oscar","family":"Huertas","sequence":"additional","affiliation":[{"name":"SOM Innovation Biotech SA","place":["Barcelona, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trond-Andr\u00e9","family":"Kr\u00e5kenes","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, University of Bergen","place":["Bergen, Norway"]},{"name":"Department of Neurology, Neuro-SysMed, Haukeland University Hospital","place":["Bergen, Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Knut","family":"Teigen","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, University of Bergen","place":["Bergen, Norway"]},{"name":"Department of Neurology, Neuro-SysMed, Haukeland University Hospital","place":["Bergen, Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Panigone","sequence":"additional","affiliation":[{"name":"SOM Innovation Biotech SA","place":["Barcelona, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rossella","family":"Medori","sequence":"additional","affiliation":[{"name":"SOM Innovation Biotech SA","place":["Barcelona, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1016\/j.nurt.2008.01.008","article-title":"Symptomatic treatment of Huntington disease","volume":"5","author":"Adam","year":"2008","journal-title":"Neurotherapeutics"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1135","DOI":"10.1007\/s00702-007-0745-1","article-title":"Role of alpha adrenoceptors in the nucleus accumbens in the control of accumbal noradrenaline efflux: a microdialysis study with freely moving rats","volume":"114","author":"Aono","year":"2007","journal-title":"J. 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