期刊
CHEMMEDCHEM
卷 4, 期 3, 页码 400-405出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.200800421
关键词
agonists; anticonvulsants; binding; glycosylation; neurotensin
资金
- Epilepsy Research Foundation
- University of Utah Startup Funds
- Anticonvulsant Screening Program (ASP)
- NIH [R21 NS055845, GM 48677]
Neurotensin (NT) is an endogenous neuropeptide involved in a variety of central and peripheral neuromodulatory effects. Herein we show the effects of site-specific glycosylation on the in vitro and in vivo pharmacological properties of this neuropeptide. NT analogues containing O-linked disaccharides (beta-melibiose and alpha-TF antigen) or beta-lactose units linked by a PEG(3) spacer were designed and chemically synthesized using Fmoc chemistry. For the latter analogue, Fmoc-Glu-(beta-Lac-PEG(3)-amide) was prepared. Our results indicate that the addition of the disaccharides does not negatively affect the sub-nanomolar affinity or the low-nanomolar agonist potency for the neurotensin receptor subtype 1 (NTS1). Interestingly, three glycosylated analogues exhibited sub-picomolar potency in the 6 Hz limbic seizure mouse model of pharmacoresistant epilepsy following intracerebroventricular administration. Our results suggest for the first time that chemically modified NT analogues may lead to novel antiepileptic therapies.
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