Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 53, Issue 12, Pages 4623-4632Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm100092s
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Funding
- National Institutes of Health, National Institute of General Medical Sciences [GM-079044]
- National Institutes of Health, National Center for Research Resources [C06 RR015455]
- Office Of The Director
- EPSCoR [919440] Funding Source: National Science Foundation
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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 IC50 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 pharmacokinctic/pharmacodynamic dichotomy is discussed. Compound 1 is a candidate for development as a first-in-class analgesic.
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