Abstract
AbstractA new class of GABA reuptake inhibitors with sterically demanding, highly rigid tricyclic cage structures as the lipophilic domain was synthesized and investigated in regard to their biological activity at the murine GABA transporters (mGAT1–mGAT4). The construction of these compounds, consisting of nipecotic acid, a symmetric tricyclic amine, and a plain hydrocarbon linker connecting the two subunits via their amino nitrogens, was accomplished via reductive amination of a nipecotic acid derivative with an N-alkyl substituent displaying a terminal aldehyde function with tricyclic secondary amines. The target compounds varied with regard to spacer length, the bridge size of one of the bridges, and the substituents of the tricyclic skeleton to study the impact of these changes on their potency. Among the tested compounds nipecotic acid ethyl ester derivates with phenyl residues attached to the cage subunit showed reasonable inhibitory potency and subtype selectivity in favor of mGAT3 and mGAT4, respectively.
Publisher
Springer Science and Business Media LLC
Subject
Organic Chemistry,General Pharmacology, Toxicology and Pharmaceutics
Reference64 articles.
1. Guzmán BCF, Vinnakota C, Govindpani K, Waldvogel HJ, Faull RLM, Kwakowsky A. The GABAergic system as a therapeutic target for Alzheimer’s disease. J Neurochem. 2018;146:649–69.
2. Lanctot KL, Herrmann N, Mazzotta P, Khan LR, Ingber N. GABAergic function in Alzheimer’s disease: evidence for dysfunction and potential as a therapeutic target for the treatment of behavioural and psychological symptoms of dementia. Can J Psychiatry. 2004;49:439–53.
3. Kalueff AV, Nutt DJ. Role of GABA in anxiety and depression. Depression Anxiety. 2007;24:495–517.
4. Kleppner SR, Tobin AJ. GABA signalling: therapeutic targets for epilepsy, Parkinson’s disease and Huntington’s disease. Expert Opin Ther Targets. 2001;5:219–39.
5. Treimann DM. GABAergic mechanisms in epilepsy. Epilepsia. 2001;42:8–12.
Cited by
1 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献