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 | Francis M Hughes Jr, Brooke E Shaner, Lisa A May, Lyndsay Zotian, Justin O Brower, R Jeremy Woods, Michael Cash, Dustin Morrow, Fabienne Massa, Jean Mazella, Thomas A Dix |
| Journal | Journal of medicinal chemistry (J Med Chem) Vol. 53 Issue 12 Pg. 4623-32 (Jun 24 2010) ISSN: 1520-4804 [Electronic] United States |
| PMID | 20481538 (Publication Type: Journal Article, Research Support, N.I.H., Extramural) |
| Chemical References |
|
| Topics |
|
Join CureHunter, for free Research Interface BASIC access!
Realize the full power of the drug-disease research graph!