(2S,3R)β-methyl-2′,6′-dimethyltyrosine-L- tetrahydroisoquinoline-3-carboxylic acid [(2S,3R)TMT-L-Tic-OH] is a potent, selective δ opioid receptor antagonist in mouse brain

Keiko Hosohata, Eva V. Varga, Josue Alfaro-Lopez, Xuejun Tang, Todd W. Vanderah, Frank Porreca, Victor J. Hruby, William R. Roeske, Henry I. Yamamura

Research output: Research - peer-reviewArticle

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Abstract

The constrained opioid peptide (2S,3R)β-methyl-2′,6′-dimethyltyrosine-L- tetrahydroisoquinoline-3-carboxylic acid [(2S,3R)TMT-L-Tic-OH] exhibits high affinity and selectivity for the δ-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]GTPγS) 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. δ-(SNC80; (+)-4-[(αR)-α-((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]GTPγS 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]GTP±S binding in mouse brain membranes but dose dependently shifted the dose-response curve of SNC80 to the right, with a Ke 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 withdrawal latencies in either nociceptive tests. (2S,3R)TMT-L-Tic-OH (30 nmol/mouse) attenuated deltorphin II- but not DAMGOmediated 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 δ-opioid antagonist in mouse brain.

LanguageEnglish (US)
Pages683-688
Number of pages6
JournalJournal of Pharmacology and Experimental Therapeutics
Volume304
Issue number2
DOIs
StatePublished - Feb 1 2003

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delta Opioid Receptor
Narcotic Antagonists
Brain
methyl-2',6'-dimethyltyrosinyltetrahydroisoquinoline-3-carboxylic acid
Membranes
Ala(2)-MePhe(4)-Gly(5)-enkephalin
Opioid Analgesics
4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide
glycyl-glycyl-glycyl-glycine
Opioid Peptides
Enkephalins
Guanosine Triphosphate
GTP-Binding Proteins
Tail
Hot Temperature
Pharmacology
Injections
Water
Ala(2)-deltorphin II
In Vitro Techniques

ASJC Scopus subject areas

  • Pharmacology

Cite this

@article{83d951b992f84f3d8eea3d9c7b52c166,
title = "(2S,3R)β-methyl-2′,6′-dimethyltyrosine-L- tetrahydroisoquinoline-3-carboxylic acid [(2S,3R)TMT-L-Tic-OH] is a potent, selective δ opioid receptor antagonist in mouse brain",
abstract = "The constrained opioid peptide (2S,3R)β-methyl-2′,6′-dimethyltyrosine-L- tetrahydroisoquinoline-3-carboxylic acid [(2S,3R)TMT-L-Tic-OH] exhibits high affinity and selectivity for the δ-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]GTPγS) 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. δ-(SNC80; (+)-4-[(αR)-α-((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]GTPγS 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]GTP±S binding in mouse brain membranes but dose dependently shifted the dose-response curve of SNC80 to the right, with a Ke 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 withdrawal latencies in either nociceptive tests. (2S,3R)TMT-L-Tic-OH (30 nmol/mouse) attenuated deltorphin II- but not DAMGOmediated 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 δ-opioid antagonist in mouse brain.",
author = "Keiko Hosohata and Varga, {Eva V.} and Josue Alfaro-Lopez and Xuejun Tang and Vanderah, {Todd W.} and Frank Porreca and Hruby, {Victor J.} and Roeske, {William R.} and Yamamura, {Henry I.}",
year = "2003",
month = "2",
doi = "10.1124/jpet.102.042929",
volume = "304",
pages = "683--688",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "2",

}

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T1 - (2S,3R)β-methyl-2′,6′-dimethyltyrosine-L- tetrahydroisoquinoline-3-carboxylic acid [(2S,3R)TMT-L-Tic-OH] is a potent, selective δ opioid receptor antagonist in mouse brain

AU - Hosohata,Keiko

AU - Varga,Eva V.

AU - Alfaro-Lopez,Josue

AU - Tang,Xuejun

AU - Vanderah,Todd W.

AU - Porreca,Frank

AU - Hruby,Victor J.

AU - Roeske,William R.

AU - Yamamura,Henry I.

PY - 2003/2/1

Y1 - 2003/2/1

N2 - The constrained opioid peptide (2S,3R)β-methyl-2′,6′-dimethyltyrosine-L- tetrahydroisoquinoline-3-carboxylic acid [(2S,3R)TMT-L-Tic-OH] exhibits high affinity and selectivity for the δ-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]GTPγS) 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. δ-(SNC80; (+)-4-[(αR)-α-((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]GTPγS 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]GTP±S binding in mouse brain membranes but dose dependently shifted the dose-response curve of SNC80 to the right, with a Ke 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 withdrawal latencies in either nociceptive tests. (2S,3R)TMT-L-Tic-OH (30 nmol/mouse) attenuated deltorphin II- but not DAMGOmediated 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 δ-opioid antagonist in mouse brain.

AB - The constrained opioid peptide (2S,3R)β-methyl-2′,6′-dimethyltyrosine-L- tetrahydroisoquinoline-3-carboxylic acid [(2S,3R)TMT-L-Tic-OH] exhibits high affinity and selectivity for the δ-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]GTPγS) 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. δ-(SNC80; (+)-4-[(αR)-α-((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]GTPγS 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]GTP±S binding in mouse brain membranes but dose dependently shifted the dose-response curve of SNC80 to the right, with a Ke 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 withdrawal latencies in either nociceptive tests. (2S,3R)TMT-L-Tic-OH (30 nmol/mouse) attenuated deltorphin II- but not DAMGOmediated 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 δ-opioid antagonist in mouse brain.

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U2 - 10.1124/jpet.102.042929

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