title: Glycosylated neurotensin analogues exhibit sub-picomolar anticonvulsant potency in a pharmacoresistant model of epilepsy.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, University of Utah, 421 Wakara Way, Suite 360, Salt Lake City, UT 84112, USA.
authors.forename: Hee-Kyoung
authors.initials: HK
authors.lastname: Lee
authors.forename: Liuyin
authors.initials: L
authors.lastname: Zhang
authors.forename: Misty D
authors.initials: MD
authors.lastname: Smith
authors.forename: H Steve
authors.initials: HS
authors.lastname: White
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Bulaj
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D004827:Epilepsy / Q000188:drug therapy*; D006031:Glycosylation; D006801:Humans; D008297:Male; D051379:Mice; D009496:Neurotensin / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D011485:Protein Binding; D018028:Receptors, Neurotensin / Q000819:agonists* / Q000378:metabolism; D012640:Seizures / Q000188:drug therapy
chemical_list: D000927:Anticonvulsants; D018028:Receptors, Neurotensin; C114036:neurotensin type 1 receptor; D009496:Neurotensin