Identification and functional characterization of a stable, centrally active derivative of the neurotensin (8-13) fragment as a potential first-in-class analgesic.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Hughes, FM; Shaner, BE; May, LA; Zotian, L; Brower, JO; Woods, RJ; Cash, M; Morrow, D; Massa, F; Mazella, J; Dix, TA

Published Date

  • June 24, 2010

Published In

Volume / Issue

  • 53 / 12

Start / End Page

  • 4623 - 4632

PubMed ID

  • 20481538

Pubmed Central ID

  • 20481538

Electronic International Standard Serial Number (EISSN)

  • 1520-4804

Digital Object Identifier (DOI)

  • 10.1021/jm100092s

Language

  • eng

Conference Location

  • United States