期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 191, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2020.112149
关键词
MTDL; BPSD; Psychosis in dementia; Alzheimer's disease; Serotonin receptors; Arylsulfonamide
资金
- Adamed Pharma S.A.
- National Science Centre (NCN) [DEC-2014/15/D/NZ7/01789]
- Jagiellonian University Medical College [N42/DBS/000017]
Patients suffering from dementia experience cognitive deficits and 90% of them show non-cognitive behavioral and psychological symptoms of dementia (BPSD). The spectrum of BPSD includes agitation, depression, anxiety and psychosis. Antipsychotics, e.g. quetiapine, have been commonly used off-label to control the burdensome symptoms, though they cause serious side effects and further cognitive impairment. Therefore, the development of targeted therapy for BPSD, suitable for elderly patients, remains relevant. A multitarget-directed ligand, acting on serotonin 5-HT2A and dopamine D-2 receptors (R) and thus exerting anti-aggressive and antipsychotic activity, as well as on 5-HT(6)Rs and 5-HT(7)Rs ( potential procognitive, antidepressant and anxiolytic activity), poses a promising strategy for the treatment of BPSD. Antitargeting muscarinic M3R and hERG channel is expected to reduce the risk of side effects. We obtained a series of stereoisomeric compounds by combining 6-fluoro-1,2-benzoxazole moiety and arylsulfonamide fragment through pyrrolidin-1-yl-propyl linker. N-[(3R)-1-[3-(6-fluoro-1,2-benzoxazol-3-yl)propyl]pyrrolidin-3-yl]-1-benzothiophene-2-sulfonamide showed a substantial affinity for the targets of interest (pK(i) = 8.32-9.35) and no significant interaction with the antitargets. Functional studies revealed its antagonist efficacy (pK(B) = 7.41-9.03). The lead compound showed a promising profile of antipsychotic-like activity in amphetamine- and MK-801-induced hyperlocomotion (MED = 2.5 mg/kg), antidepressant-like, as well as anxiolytic-like activity in mice (MED = 0.312 and 1.25 mg/kg in the forced swim and four-plate tests, respectively). Notably, the novel compound didn't affect spontaneous locomotor activity, nor induced catalepsy or memory deficits (step-through passive avoidance test) in therapeutically relevant doses, which proved its benign safety profile. The overall pharmacological characteristics of the lead compound outperformed the reference drug quetiapine, making it a promising option for evaluation in the treatment of BPSD. (c) 2020 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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