Discovery of Nonracemic Amisulpride to Maximize Benefit/Risk of 5-HT7 and D2 Receptor Antagonism for the Treatment of Mood Disorders

Seth C Hopkins, Scott Wilkinson, Taryn J Corriveau, Hiroyuki Nishikawa, Keiko Nakamichi, Antony Loebel, Kenneth S Koblan, Seth C Hopkins, Scott Wilkinson, Taryn J Corriveau, Hiroyuki Nishikawa, Keiko Nakamichi, Antony Loebel, Kenneth S Koblan

Abstract

In contrast to the dose-occupancy relationship in the treatment of schizophrenia, the minimal effective level of dopamine receptor 2 (D2R) blockade for antipsychotics in the treatment of bipolar depression is unknown. Lower doses aimed at reducing extrapyramidal side effects must be balanced against the need to retain the therapeutic benefit of D2R blockade on emergent cycling, mixed, manic, anxiety, and/or psychotic symptoms. Dose-reductions intended to lower D2R blockade, however, could also decrease concomitant serotonin receptor antagonism and its potential benefit on depressive symptoms. Here, we uncoupled the potential antidepressant activity in amisulpride, driven by 5-HT7 receptor (5-HT7R) antagonism, from the D2R-mediated antipsychotic activity by discovering that each enantiomer favors a different receptor. Aramisulpride was more potent at 5-HT7R relative to esamisulpride (Ki 47 vs. 1,900 nM, respectively), whereas esamisulpride was more potent at D2R (4.0 vs. 140 nM). We hypothesized that a nonracemic ratio might achieve greater 5-HT7R-mediated antidepressant effects at a lower level of D2R blockade. The dose-occupancy relationship of esamisulpride at D2R was determined by positron emission tomography (PET) imaging in human volunteers. Separately the dose-relationship of aramisulpride was established in humans using suppression of rapid eye movement (REM) sleep as a marker of 5-HT7R antagonism. These results led to the discovery of an 85:15 ratio of aramisulpride to esamisulpride (SEP-4199) that maximizes the potential for antidepressant benefit of aramisulpride via 5-HT7R and reduces esamisulpride to minimize D2R-related extrapyramidal side effects while still retaining D2R-mediated effects predicted to provide benefit in bipolar depression. The antidepressant efficacy of SEP-4199 was recently confirmed in a proof-of-concept trial for the treatment of bipolar depression (NCT03543410).

Conflict of interest statement

S.C.H., S.W., T.J.C., A.L., and K.S.K. are employees of Sunovion Pharmaceuticals Inc. H.N. and K.N. are employees of Sumitomo Dainippon Pharma Co., Ltd.

© 2021 Sunovion Pharmaceuticals Inc. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1
Figure 1
(a) Radioligand binding in vitro of amisulpride enantiomers to recombinantly expressed human dopamine receptor 2 (D2R) and 5‐HT7 receptor (5HT7R) demonstrate stereoselectivity. Radioligand displacement was determined in triplicate as a function of increasing drug concentrations, where symbols represent the average and SD. (b) Relative potencies (Ki values) were determined in triplicate as a function of increasing aramisulpride content, where potency ratio is the Ki for 5‐HT7 divided by the Ki for D2, and average Ki is noted ± SEM.
Figure 2
Figure 2
Forced Swim Test: rats were administered vehicle, imipramine, or aramisulpride at 23.5 hours, 5 hours and 1 hour prior to testing. Values are mean ± SEM, 18 animals per treatment group. ##P < 0.01 vs. vehicle (two‐sided t‐test), *P < 0.05 or **P < 0.01 vs. vehicle (parametric Dunnett’s multiple comparison test, two‐sided). Rat Sleep electroencephalogram (EEG): rats were administered aramisulpride or vehicle 10 minutes before the beginning of the recording light phase. EEG and electromyogram (EMG) were recorded for 6 hours starting at the beginning of the light phase and rapid eye movement (REM) sleep time was measured. Data are expressed as mean ± SEM, n = 7 animals. *P < 0.05, **P < 0.01 (two‐way analysis of variance (ANOVA) followed by post hoc parametric Dunnett multiple comparison test).
Figure 3
Figure 3
(a) Dopamine receptor 2 (D2R) occupancies for esamisulpride (red symbols) and SEP‐4199 (blue symbols) are shown from studies 1 and 3. (b) Suppression of rapid eye movement (REM) sleep (green symbols) is shown for single doses of aramisulpride, difference vs. placebo, ±90% confidence interval (CI). (c) Horizontal bars indicate intervals of dose‐effect for esamisulpride discovered in positron emission tomography (PET) imaging study 1 to occupy 30–50% D2R (horizontal black bars) and dose ranges of aramisulpride discovered in polysomnography (PSG) study 2 to produce serotonergic effects on REM suppression (horizontal grey bars). Intervals of dose‐effect are expressed according to an x‐axis of total amisulpride enantiomers (both aramisulpride and esamisulpride) RS, R‐ and S‐enantiomers.

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