Cargando…

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

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Hopkins, Seth C., Wilkinson, Scott, Corriveau, Taryn J., Nishikawa, Hiroyuki, Nakamichi, Keiko, Loebel, Antony, Koblan, Kenneth S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453756/
https://www.ncbi.nlm.nih.gov/pubmed/33961287
http://dx.doi.org/10.1002/cpt.2282
_version_ 1784570339228909568
author Hopkins, Seth C.
Wilkinson, Scott
Corriveau, Taryn J.
Nishikawa, Hiroyuki
Nakamichi, Keiko
Loebel, Antony
Koblan, Kenneth S.
author_facet Hopkins, Seth C.
Wilkinson, Scott
Corriveau, Taryn J.
Nishikawa, Hiroyuki
Nakamichi, Keiko
Loebel, Antony
Koblan, Kenneth S.
author_sort Hopkins, Seth C.
collection PubMed
description 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).
format Online
Article
Text
id pubmed-8453756
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher John Wiley and Sons Inc.
record_format MEDLINE/PubMed
spelling pubmed-84537562021-09-27 Discovery of Nonracemic Amisulpride to Maximize Benefit/Risk of 5‐HT7 and D2 Receptor Antagonism for the Treatment of Mood Disorders Hopkins, Seth C. Wilkinson, Scott Corriveau, Taryn J. Nishikawa, Hiroyuki Nakamichi, Keiko Loebel, Antony Koblan, Kenneth S. Clin Pharmacol Ther Research 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). John Wiley and Sons Inc. 2021-06-12 2021-09 /pmc/articles/PMC8453756/ /pubmed/33961287 http://dx.doi.org/10.1002/cpt.2282 Text en © 2021 Sunovion Pharmaceuticals Inc. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Research
Hopkins, Seth C.
Wilkinson, Scott
Corriveau, Taryn J.
Nishikawa, Hiroyuki
Nakamichi, Keiko
Loebel, Antony
Koblan, Kenneth S.
Discovery of Nonracemic Amisulpride to Maximize Benefit/Risk of 5‐HT7 and D2 Receptor Antagonism for the Treatment of Mood Disorders
title Discovery of Nonracemic Amisulpride to Maximize Benefit/Risk of 5‐HT7 and D2 Receptor Antagonism for the Treatment of Mood Disorders
title_full Discovery of Nonracemic Amisulpride to Maximize Benefit/Risk of 5‐HT7 and D2 Receptor Antagonism for the Treatment of Mood Disorders
title_fullStr Discovery of Nonracemic Amisulpride to Maximize Benefit/Risk of 5‐HT7 and D2 Receptor Antagonism for the Treatment of Mood Disorders
title_full_unstemmed Discovery of Nonracemic Amisulpride to Maximize Benefit/Risk of 5‐HT7 and D2 Receptor Antagonism for the Treatment of Mood Disorders
title_short Discovery of Nonracemic Amisulpride to Maximize Benefit/Risk of 5‐HT7 and D2 Receptor Antagonism for the Treatment of Mood Disorders
title_sort discovery of nonracemic amisulpride to maximize benefit/risk of 5‐ht7 and d2 receptor antagonism for the treatment of mood disorders
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453756/
https://www.ncbi.nlm.nih.gov/pubmed/33961287
http://dx.doi.org/10.1002/cpt.2282
work_keys_str_mv AT hopkinssethc discoveryofnonracemicamisulpridetomaximizebenefitriskof5ht7andd2receptorantagonismforthetreatmentofmooddisorders
AT wilkinsonscott discoveryofnonracemicamisulpridetomaximizebenefitriskof5ht7andd2receptorantagonismforthetreatmentofmooddisorders
AT corriveautarynj discoveryofnonracemicamisulpridetomaximizebenefitriskof5ht7andd2receptorantagonismforthetreatmentofmooddisorders
AT nishikawahiroyuki discoveryofnonracemicamisulpridetomaximizebenefitriskof5ht7andd2receptorantagonismforthetreatmentofmooddisorders
AT nakamichikeiko discoveryofnonracemicamisulpridetomaximizebenefitriskof5ht7andd2receptorantagonismforthetreatmentofmooddisorders
AT loebelantony discoveryofnonracemicamisulpridetomaximizebenefitriskof5ht7andd2receptorantagonismforthetreatmentofmooddisorders
AT koblankenneths discoveryofnonracemicamisulpridetomaximizebenefitriskof5ht7andd2receptorantagonismforthetreatmentofmooddisorders