Faculty Collaboration Database

N-(4-Bromo-2,5-Dimethoxyphenethyl)-6-(4-Phenylbutoxy)Hexan-1-Amine (XOB): A Novel Phenylalkylamine Antagonist of Serotonin 2A Receptors and Voltage-Gated Sodium Channels. Mol Pharmacol 2024 Jul 17;106(2):92-106

Date

06/01/2024

Pubmed ID

38821630

Pubmed Central ID

PMC11254453

DOI

10.1124/molpharm.123.000837

Scopus ID

2-s2.0-85199223647 (requires institutional sign-in at Scopus site)

Abstract

Bipolar disorder impacts millions of patients in the United States but the mechanistic understanding of its pathophysiology and therapeutics is incomplete. Atypical antipsychotic serotonin_2A (5-HT_2A) receptor antagonists, such as quetiapine and olanzapine, and mood-stabilizing voltage-gated sodium channel (VGSC) blockers, such as lamotrigine, carbamazepine, and valproate, show therapeutic synergy and are often prescribed in combination for the treatment of bipolar disorder. Combination therapy is a complex task for clinicians and patients, often resulting in unexpected difficulties with dosing, drug tolerances, and decreased patient compliance. Thus, an unmet need for bipolar disorder treatment is to develop a therapeutic agent that targets both 5-HT_2A receptors and VGSCs. Toward this goal, we developed a novel small molecule that simultaneously antagonizes 5-HT_2A receptors and blocks sodium current. The new compound, N-(4-bromo-2,5-dimethoxyphenethyl)-6-(4-phenylbutoxy)hexan-1-amine (XOB) antagonizes 5-HT-stimulated, G_q-mediated, calcium flux at 5-HT_2A receptors at low micromolar concentrations while displaying negligible affinity and activity at 5-HT_1A, 5-HT_2B, and 5-HT_2C receptors. At similar concentrations, XOB administration inhibits sodium current in heterologous cells and results in reduced action potential (AP) firing and VGSC-related AP properties in mouse prefrontal cortex layer V pyramidal neurons. Thus, XOB represents a new, proof-of-principle tool that can be used for future preclinical investigations and therapeutic development. This polypharmacology approach of developing a single molecule to act upon two targets, which are currently independently targeted by combination therapies, may lead to safer alternatives for the treatment of psychiatric disorders that are increasingly being found to benefit from the simultaneous targeting of multiple receptors. SIGNIFICANCE STATEMENT: The authors synthesized a novel small molecule (XOB) that simultaneously antagonizes two key therapeutic targets of bipolar disorder, 5-HT_2A receptors and voltage-gated sodium channels, in heterologous cells, and inhibits the intrinsic excitability of mouse prefrontal cortex layer V pyramidal neurons in brain slices. XOB represents a valuable new proof-of-principle tool for future preclinical investigations and provides a novel molecular approach to the pharmacological treatment of complex neuropsychiatric disease, which often requires a combination of therapeutics for sufficient patient benefit.

Author List

Denomme N, Hernandez CC, Bock HA, Ohana RF, Bakshi S, Sherwood AM, McCorvy JD, Daley PF, Callaway WB, Hull JM, Alt A, Isom LL, Cozzi NV

Author

John McCorvy PhD Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Cricetulus
HEK293 Cells
Humans
Male
Mice
Mice, Inbred C57BL
Receptor, Serotonin, 5-HT2A
Serotonin 5-HT2 Receptor Antagonists
Voltage-Gated Sodium Channels