title: Identification and functional characterization of a stable, centrally active derivative of the neurotensin (8-13) fragment as a potential first-in-class analgesic.
abstract: The neurotensin hexapapetide fragment NT(8-13) is a potent analgesic when administered directly to the central nervous system but does not cross the blood-brain barrier. A total of 43 novel derivatives of NT(8-13) were evaluated, with one, ABS212 (1), being most active in four rat models of pain when administered peripherally. Compound 1 binds to human neurotensin receptors 1 and 2 with IC(50) of 10.6 and 54.2 nM, respectively, and tolerance to the compound in a rat pain model did not develop after 12 days of daily administration. When it was administered peripherally, serum levels and neurotensin receptor binding potency of 1 peaked within 5 min and returned to baseline within 90-120 min; however, analgesic activity remained near maximum for >240 min. This could be due to its metabolism into an active fragment; however, all 4- and 5-mer hydrolysis products were inactive. This pharmacokinetic/pharmacodynamic dichotomy is discussed. Compound 1 is a candidate for development as a first-in-class analgesic.
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, South Carolina College of Pharmacy, Medical University of South Carolina Campus, 280 Calhoun Street, Charleston, South Carolina 29425-2303, USA.
authors.forename: Francis M
authors.initials: FM
authors.lastname: Hughes
authors.forename: Brooke E
authors.initials: BE
authors.lastname: Shaner
authors.forename: Lisa A
authors.initials: LA
authors.lastname: May
authors.forename: Lyndsay
authors.initials: L
authors.lastname: Zotian
authors.forename: Justin O
authors.initials: JO
authors.lastname: Brower
authors.forename: R Jeremy
authors.initials: RJ
authors.lastname: Woods
authors.forename: Michael
authors.initials: M
authors.lastname: Cash
authors.forename: Dustin
authors.initials: D
authors.lastname: Morrow
authors.forename: Fabienne
authors.initials: F
authors.lastname: Massa
authors.forename: Jean
authors.initials: J
authors.lastname: Mazella
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Dix
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D001831:Body Temperature / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D004361:Drug Tolerance; D006801:Humans; D008297:Male; D009496:Neurotensin / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010147:Pain Measurement; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018028:Receptors, Neurotensin / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C550632:ABS 212; D000700:Analgesics; C490985:NTSR2 protein, human; D009842:Oligopeptides; D010446:Peptide Fragments; D018028:Receptors, Neurotensin; C114036:neurotensin type 1 receptor; D009496:Neurotensin; C054381:neurotensin (8-13); D002118:Calcium