Abstract
In order to target behavioral and psychological symptoms of dementia (BPSD), we used molecular modeling-assisted design to obtain novel multifunctional arylsulfonamide derivatives that potently antagonize 5-HT(6/7/2A) and D2 receptors, without interacting with M1 receptors and hERG channels. In vitro studies confirmed their antagonism of 5-HT(7/2A) and D2 receptors and weak interactions with key antitargets (M1R and hERG) associated with side effects. Marked 5-HT6 receptor affinities were also observed, notably for 6-fluoro-3-(piperidin-4-yl)-1,2-benzoxazole derivatives connected by a 3-4 unit alkyl linker with mono- or bicyclic, lipophilic arylsulfonamide moieties. N-[4-[4-(6-Fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]butyl]benzothiophene-2-sulfonamide (72) was characterized in vitro on 14 targets and antitargets. It displayed dual blockade of 5-HT6 and D2 receptors and negligible interactions at hERG and M1 receptors. Unlike reference antipsychotics, 72 displayed marked antipsychotic and antidepressant activity in rats after oral administration, in the absence of cognitive or motor impairment. This profile is particularly attractive when targeting a fragile, elderly BPSD patient population.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antidepressive Agents / chemical synthesis*
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Antidepressive Agents / chemistry
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Antidepressive Agents / pharmacology
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Antipsychotic Agents / chemical synthesis*
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Antipsychotic Agents / chemistry
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Antipsychotic Agents / pharmacology
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Avoidance Learning / drug effects
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Benzoxazoles / chemical synthesis*
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Benzoxazoles / chemistry
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Benzoxazoles / pharmacology
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CHO Cells
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Catalepsy / chemically induced
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Cricetulus
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Dementia / drug therapy*
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Dementia / psychology
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Dopamine D2 Receptor Antagonists
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HEK293 Cells
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Humans
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Male
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Models, Molecular
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Motor Activity / drug effects
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Radioligand Assay
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Rats, Wistar
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Receptors, Serotonin / metabolism*
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Serotonin Antagonists / chemical synthesis*
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Serotonin Antagonists / chemistry
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Serotonin Antagonists / pharmacology
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis*
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Sulfonamides / chemistry
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Sulfonamides / pharmacology
Substances
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Antidepressive Agents
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Antipsychotic Agents
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Benzoxazoles
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Dopamine D2 Receptor Antagonists
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N-(4-(4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl)butyl)benzothiophene-2-sulfonamide
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Receptors, Serotonin
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Serotonin Antagonists
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Sulfonamides
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serotonin 6 receptor
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serotonin 7 receptor