title: (2S,3R) beta-methyl-2',6'-dimethyltyrosine-L-tetrahydroisoquinoline-3-carboxylic acid [(2S,3R)TMT-L-Tic-OH] is a potent, selective delta-opioid receptor antagonist in mouse brain.
abstract: The constrained opioid peptide (2S,3R)beta-methyl-2',6'-dimethyltyrosine-L-tetrahydroisoquinoline-3-carboxylic acid [(2S,3R)TMT-L-Tic-OH] exhibits high affinity and selectivity for the delta-opioid receptors (). In the present study, we examined the pharmacological properties of (2S,3R)TMT-L-Tic-OH in mouse brain. A 5'-O-(3-[(35)S]thiotriphosphate) ([(35)S]GTP gamma S) 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. delta- (SNC80; (+)-4-[(alpha R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxy-benzyl]-N,N-diethyl-benzamide) or mu- (DAMGO; [D-Ala(2), Me-Phe(4),Gly(ol)(5)]enkephalin) selective opioid full agonists stimulated [(35)S]GTP gamma S 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 [(35)S]GTP gamma S 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 mu-selective opioid agonist, DAMGO. Warm water (55 degrees 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 withdrawal 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 delta-opioid antagonist in mouse brain.
authors.affiliation: Department of Pharmacology, University of Arizona, Tucson, Arizona 85724, USA.
authors.forename: Keiko
authors.initials: K
authors.lastname: Hosohata
authors.forename: Eva V
authors.initials: EV
authors.lastname: Varga
authors.forename: Josue
authors.initials: J
authors.lastname: Alfaro-Lopez
authors.forename: Xuejun
authors.initials: X
authors.lastname: Tang
authors.forename: Todd W
authors.initials: TW
authors.lastname: Vanderah
authors.forename: Frank
authors.initials: F
authors.lastname: Porreca
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Hruby
authors.forename: William R
authors.initials: WR
authors.lastname: Roeske
authors.forename: Henry I
authors.initials: HI
authors.lastname: Yamamura
mesh_terms: D000701:Analgesics, Opioid / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000378:metabolism / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism / Q000494:pharmacology; D007546:Isoquinolines / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009292:Narcotic Antagonists / Q000378:metabolism / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D044005:Tetrahydroisoquinolines; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000701:Analgesics, Opioid; D007546:Isoquinolines; D009292:Narcotic Antagonists; D017465:Receptors, Opioid, delta; D044005:Tetrahydroisoquinolines; C122084:methyl-2',6'-dimethyltyrosinyltetrahydroisoquinoline-3-carboxylic acid; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D014443:Tyrosine