Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland; Adamed Pharma S.A., Pienkow, 6A Mariana Adamkiewicza Street, 05-152, Czosnów, Poland.
Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland; Adamed Pharma S.A., Pienkow, 6A Mariana Adamkiewicza Street, 05-152, Czosnów, Poland.
Eur J Med Chem. 2020 Apr 1;191:112149. doi: 10.1016/j.ejmech.2020.112149. Epub 2020 Feb 18.
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-HT and dopamine D receptors (R) and thus exerting anti-aggressive and antipsychotic activity, as well as on 5-HTRs and 5-HTRs (potential pro-cognitive, antidepressant and anxiolytic activity), poses a promising strategy for the treatment of BPSD. Antitargeting muscarinic MR 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 = 8.32-9.35) and no significant interaction with the antitargets. Functional studies revealed its antagonist efficacy (pK = 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.
患有痴呆症的患者会出现认知功能障碍，其中 90%的患者会表现出非认知行为和心理症状（BPSD）。BPSD 的症状谱包括激越、抑郁、焦虑和精神病。抗精神病药，如喹硫平，已被广泛用于非适应证，以控制负担过重的症状，尽管它们会引起严重的副作用并进一步导致认知障碍。因此，针对 BPSD 开发适合老年患者的靶向治疗仍然具有相关性。一种多靶点配体，作用于 5-HT 和多巴胺 D 受体（R），从而发挥抗激越和抗精神病作用，以及 5-HTRs 和 5-HTRs（潜在的促认知、抗抑郁和抗焦虑作用），为治疗 BPSD 提供了一种有前途的策略。靶向毒蕈碱 MR 和 hERG 通道有望降低副作用风险。我们通过将 6-氟-1,2-苯并恶唑部分和芳基磺酰胺片段结合在吡咯烷-1-基-丙基连接子上，获得了一系列立体异构体化合物。N-[(3R)-1-[3-(6-氟-1,2-苯并恶唑-3-基)丙基]吡咯烷-3-基]-1-苯并噻吩-2-磺酰胺对感兴趣的靶点表现出显著的亲和力（pK = 8.32-9.35），与拮抗靶点无明显相互作用。功能研究显示其拮抗剂效能（pK = 7.41-9.03）。该先导化合物在安非他命和 MK-801 诱导的过度活跃（MED = 2.5 mg/kg）、抗抑郁和抗焦虑行为（在强迫游泳和四板测试中，MED 分别为 0.312 和 1.25 mg/kg）方面表现出有希望的抗精神病样活性。值得注意的是，该新型化合物在治疗相关剂量下不影响自发运动活动，也不会引起僵住或记忆缺陷（穿梭被动回避测试），证明其具有良性的安全性特征。该先导化合物的整体药理特征优于参考药物喹硫平，使其成为评估治疗 BPSD 的有希望的选择。
