Discovery, synthesis, and molecular pharmacology of selective positive allosteric modulators of the δ-opioid receptor

Neil T Burford, Kathryn E Livingston, Meritxell Canals, Molly R Ryan, Lauren M L Budenholzer, Ying Han, Yi Shang, John J Herbst, Jonathan O'Connell, Martyn Banks, Litao Zhang, Marta Filizola, Daniel L Bassoni, Tom S Wehrman, Arthur Christopoulos, John R Traynor, Samuel W Gerritz, Andrew Alt

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31 Citations (Scopus)

Abstract

Allosteric modulators of G protein-coupled receptors (GPCRs) have a number of potential advantages compared to agonists or antagonists that bind to the orthosteric site of the receptor. These include the potential for receptor selectivity, maintenance of the temporal and spatial fidelity of signaling in vivo, the ceiling effect of the allosteric cooperativity which may prevent overdose issues, and engendering bias by differentially modulating distinct signaling pathways. Here we describe the discovery, synthesis, and molecular pharmacology of δ-opioid receptor-selective positive allosteric modulators (δ PAMs). These δ PAMs increase the affinity and/or efficacy of the orthosteric agonists leu-enkephalin, SNC80 and TAN67, as measured by receptor binding, G protein activation, β-arrestin recruitment, adenylyl cyclase inhibition, and extracellular signal-regulated kinases (ERK) activation. As such, these compounds are useful pharmacological tools to probe the molecular pharmacology of the δ receptor and to explore the therapeutic potential of δ PAMs in diseases such as chronic pain and depression.
Original languageEnglish
Pages (from-to)4220-4229
Number of pages10
JournalJournal of Medicinal Chemistry
Volume58
Issue number10
DOIs
Publication statusPublished - 2015

Cite this

Burford, N. T., Livingston, K. E., Canals, M., Ryan, M. R., Budenholzer, L. M. L., Han, Y., ... Alt, A. (2015). Discovery, synthesis, and molecular pharmacology of selective positive allosteric modulators of the δ-opioid receptor. Journal of Medicinal Chemistry, 58(10), 4220-4229. https://doi.org/10.1021/acs.jmedchem.5b00007
Burford, Neil T ; Livingston, Kathryn E ; Canals, Meritxell ; Ryan, Molly R ; Budenholzer, Lauren M L ; Han, Ying ; Shang, Yi ; Herbst, John J ; O'Connell, Jonathan ; Banks, Martyn ; Zhang, Litao ; Filizola, Marta ; Bassoni, Daniel L ; Wehrman, Tom S ; Christopoulos, Arthur ; Traynor, John R ; Gerritz, Samuel W ; Alt, Andrew. / Discovery, synthesis, and molecular pharmacology of selective positive allosteric modulators of the δ-opioid receptor. In: Journal of Medicinal Chemistry. 2015 ; Vol. 58, No. 10. pp. 4220-4229.
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abstract = "Allosteric modulators of G protein-coupled receptors (GPCRs) have a number of potential advantages compared to agonists or antagonists that bind to the orthosteric site of the receptor. These include the potential for receptor selectivity, maintenance of the temporal and spatial fidelity of signaling in vivo, the ceiling effect of the allosteric cooperativity which may prevent overdose issues, and engendering bias by differentially modulating distinct signaling pathways. Here we describe the discovery, synthesis, and molecular pharmacology of δ-opioid receptor-selective positive allosteric modulators (δ PAMs). These δ PAMs increase the affinity and/or efficacy of the orthosteric agonists leu-enkephalin, SNC80 and TAN67, as measured by receptor binding, G protein activation, β-arrestin recruitment, adenylyl cyclase inhibition, and extracellular signal-regulated kinases (ERK) activation. As such, these compounds are useful pharmacological tools to probe the molecular pharmacology of the δ receptor and to explore the therapeutic potential of δ PAMs in diseases such as chronic pain and depression.",
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Burford, NT, Livingston, KE, Canals, M, Ryan, MR, Budenholzer, LML, Han, Y, Shang, Y, Herbst, JJ, O'Connell, J, Banks, M, Zhang, L, Filizola, M, Bassoni, DL, Wehrman, TS, Christopoulos, A, Traynor, JR, Gerritz, SW & Alt, A 2015, 'Discovery, synthesis, and molecular pharmacology of selective positive allosteric modulators of the δ-opioid receptor', Journal of Medicinal Chemistry, vol. 58, no. 10, pp. 4220-4229. https://doi.org/10.1021/acs.jmedchem.5b00007

Discovery, synthesis, and molecular pharmacology of selective positive allosteric modulators of the δ-opioid receptor. / Burford, Neil T; Livingston, Kathryn E; Canals, Meritxell; Ryan, Molly R; Budenholzer, Lauren M L; Han, Ying; Shang, Yi; Herbst, John J; O'Connell, Jonathan; Banks, Martyn; Zhang, Litao; Filizola, Marta; Bassoni, Daniel L; Wehrman, Tom S; Christopoulos, Arthur; Traynor, John R; Gerritz, Samuel W; Alt, Andrew.

In: Journal of Medicinal Chemistry, Vol. 58, No. 10, 2015, p. 4220-4229.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Discovery, synthesis, and molecular pharmacology of selective positive allosteric modulators of the δ-opioid receptor

AU - Burford, Neil T

AU - Livingston, Kathryn E

AU - Canals, Meritxell

AU - Ryan, Molly R

AU - Budenholzer, Lauren M L

AU - Han, Ying

AU - Shang, Yi

AU - Herbst, John J

AU - O'Connell, Jonathan

AU - Banks, Martyn

AU - Zhang, Litao

AU - Filizola, Marta

AU - Bassoni, Daniel L

AU - Wehrman, Tom S

AU - Christopoulos, Arthur

AU - Traynor, John R

AU - Gerritz, Samuel W

AU - Alt, Andrew

PY - 2015

Y1 - 2015

N2 - Allosteric modulators of G protein-coupled receptors (GPCRs) have a number of potential advantages compared to agonists or antagonists that bind to the orthosteric site of the receptor. These include the potential for receptor selectivity, maintenance of the temporal and spatial fidelity of signaling in vivo, the ceiling effect of the allosteric cooperativity which may prevent overdose issues, and engendering bias by differentially modulating distinct signaling pathways. Here we describe the discovery, synthesis, and molecular pharmacology of δ-opioid receptor-selective positive allosteric modulators (δ PAMs). These δ PAMs increase the affinity and/or efficacy of the orthosteric agonists leu-enkephalin, SNC80 and TAN67, as measured by receptor binding, G protein activation, β-arrestin recruitment, adenylyl cyclase inhibition, and extracellular signal-regulated kinases (ERK) activation. As such, these compounds are useful pharmacological tools to probe the molecular pharmacology of the δ receptor and to explore the therapeutic potential of δ PAMs in diseases such as chronic pain and depression.

AB - Allosteric modulators of G protein-coupled receptors (GPCRs) have a number of potential advantages compared to agonists or antagonists that bind to the orthosteric site of the receptor. These include the potential for receptor selectivity, maintenance of the temporal and spatial fidelity of signaling in vivo, the ceiling effect of the allosteric cooperativity which may prevent overdose issues, and engendering bias by differentially modulating distinct signaling pathways. Here we describe the discovery, synthesis, and molecular pharmacology of δ-opioid receptor-selective positive allosteric modulators (δ PAMs). These δ PAMs increase the affinity and/or efficacy of the orthosteric agonists leu-enkephalin, SNC80 and TAN67, as measured by receptor binding, G protein activation, β-arrestin recruitment, adenylyl cyclase inhibition, and extracellular signal-regulated kinases (ERK) activation. As such, these compounds are useful pharmacological tools to probe the molecular pharmacology of the δ receptor and to explore the therapeutic potential of δ PAMs in diseases such as chronic pain and depression.

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U2 - 10.1021/acs.jmedchem.5b00007

DO - 10.1021/acs.jmedchem.5b00007

M3 - Article

VL - 58

SP - 4220

EP - 4229

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

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ER -