J014 SOM3355 has an atypical profile of VMAT2 inhibition

<h3></h3> The vesicular monoamine transporter subtype 2 (VMAT2) inhibitor Tetrabenazine (TBZ) or the related compounds deutetrabenazine and valbenazine are used to treat Huntington’s chorea. While efficacious, side effects of sedation, somnolence, and the risk of worsening depression, suicidal ideation or suicidal behaviour limit their use. Using a proprietary artificial intelligence platform (SOM_AIPRO^®) SOM Innovation Biotech discovered that SOM3355 (bevantolol, Calvan^®, (±)-1-[(3,4-Dimethoxyphenethyl)amino]-3-(m-tolyloxy)-2-propanol hydrochloride) a Beta1 adrenergic antagonist used safely for nearly 30 years in the treatment of hypertension, also has potent VMAT2 inhibitory properties and penetrates the central nervous system. Using radiolabel binding and reuptake assays with human VMAT2 (hVMAT2) it was found that SOM3355 and TBZ inhibited 3H-dopamine uptake with similar potencies (IC50 of 66nM vs 32nM respectively). However, SOM3355 only displaced 3H-DHTBZ at much higher concentrations than TBZ (IC50 1353nM vs 19nM). SOM3355 also inhibited 3H-serotonin uptake to a lesser extent than TBZ (IC50 of 600nM vs 63nM). Therefore, SOM3355 has a different profile of interaction with the hVMAT2 compared to TBZ. Furthermore, SOM3355 shows inhibition of 3H-serotonin uptake by the rat VMAT subtype 1 (IC50 44nM) while TBZ had no effect (IC50&gt;10uM). In a proof-of-concept study (Gamez, Br. J. Clin Pharmacol,2022;1–9) SOM3355 significantly reduced chorea and was well tolerated. Our hypothesis is that the distinct interaction with the VMAT2 and VMAT1 underlies both the safety and efficacy of SOM3355 in the treatment of chorea in HD. SOM3355 could be described as an atypical VMAT2 inhibitor.