QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Hosohata, K. Articles by Yamamura, H. I. Search for Related Content PubMed PubMed Citation Articles by Hosohata, K. Articles by Yamamura, H. I.

NEUROPHARMACOLOGY

(2S,3R)-Methyl-2',6'-dimethyltyrosine-L-tetrahydroisoquinoline-3-carboxylic acid [(2S,3R)TMT-L-Tic-OH] Is a Potent, Selective -Opioid Receptor Antagonist in Mouse Brain

Departments of Pharmacology, Chemistry, Biochemistry, Psychiatry, and Medicine and the Sarver Heart Center, University of Arizona, Tucson, Arizona

The constrained opioid peptide (2S,3R)-methyl-2',6'-dimethylty-rosine-L-tetrahydroisoquinoline-3-carboxylic acid [(2S,3R)TMT-L-Tic-OH] exhibits high affinity and selectivity for the -opioid receptors (Liao et al., 1997). In the present study, we examined the pharmacological properties of (2S,3R)TMT-L-Tic-OH in mouse brain. A 5'-O-(3-[³⁵S]thiotriphosphate) ([³⁵S]GTPS) binding assay was used to determine the effect of (2S,3R)TMT-L-Tic-OH on G protein activity in vitro, in mouse brain membranes. -(SNC80; (+)-4-[(R)--((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxy-benzyl]-N,N-diethyl-benzamide) or µ-(DAMGO; [D-Ala², Me-Phe⁴,Gly(ol)⁵]enkephalin) selective opioid full agonists stimulated [³⁵S]GTPS binding in mouse brain membranes 150 ± 4.5% and 152 ± 5.7% over the basal level, respectively. (2S,3R)TMT-L-Tic-OH did not influence basal [³⁵S]GTPS binding in mouse brain membranes but dose dependently shifted the dose-response curve of SNC80 to the right, with a K_e value of 3.6 ± 0.7 nM. In contrast, (2S,3R)TMT-L-Tic-OH had no effect on the dose-response curve of the µ-selective opioid agonist, DAMGO. Warm water (55°C) tail-flick and radiant heat paw-withdrawal tests were used to determine the in vivo nociceptive properties of (2S,3R)TMT-L-Tic-OH in the mouse. Intracerebroventricular injection of (2S,3R)TMT-L-Tic-OH had no significant effect on with-drawal latencies in either nociceptive tests. (2S,3R)TMT-L-Tic-OH (30 nmol/mouse) attenuated deltorphin II- but not DAMGO-mediated antinociception (40 ± 13 and 100% of maximal possible effect, respectively) when administered intracerebroventricularly 10 min before the agonist. Taken together these results suggest that (2S,3R)TMT-L-Tic-OH is a potent highly selective neutral -opioid antagonist in mouse brain.

Address correspondence to: Dr. Henry I. Yamamura, Department of Pharmacology, College of Medicine, University of Arizona Health Sciences Center, Tucson, AZ 85724. E-mail: hiy{at}u.arizona.edu