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; Budenholzer, Lauren; Han, Ying; Shang, Yi; Herbst, John J.; O’Connell, Jonathan C.; Banks, Martyn; Zhang, Litao; Filizola, Marta; Bassoni, Daniel L.; Wehrman, Tom S.; Christopoulos, Arthur; Traynor, John R.; Gerritz, Samuel W.; Alt, Andrew

doi:10.1021/acs.jmedchem.5b00007

Cited by 55 publications

(75 citation statements)

References 34 publications

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“…4c,e). BMS-986187 is known to have agonist properties at higher concentrations45 and BMS-986187 alone induced a small but significant decrease in eEPSC amplitude (Fig. 4d,e; P <0.05, paired t -test).…”

Section: Resultsmentioning

confidence: 91%

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Endogenous opioids regulate moment-to-moment neuronal communication and excitability

et al. 2017

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Fear and emotional learning are modulated by endogenous opioids but the cellular basis for this is unknown. The intercalated cells (ITCs) gate amygdala output and thus regulate the fear response. Here we find endogenous opioids are released by synaptic stimulation to act via two distinct mechanisms within the main ITC cluster. Endogenously released opioids inhibit glutamate release through the δ-opioid receptor (DOR), an effect potentiated by a DOR-positive allosteric modulator. Postsynaptically, the opioids activate a potassium conductance through the μ-opioid receptor (MOR), suggesting for the first time that endogenously released opioids directly regulate neuronal excitability. Ultrastructural localization of endogenous ligands support these functional findings. This study demonstrates a new role for endogenously released opioids as neuromodulators engaged by synaptic activity to regulate moment-to-moment neuronal communication and excitability. These distinct actions through MOR and DOR may underlie the opposing effect of these receptor systems on anxiety and fear.

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Section: Resultsmentioning

confidence: 91%

“…We explored this possibility using the DOR PAM BMS-986187, which shows 100-fold selectivity for DOR over MOR and increases efficacy, potency and affinity of orthosteric ligands45. BMS-986187 (1 μM) significantly enhanced the inhibition induced by submaximal, exogenous ME (100 nM, Fig.…”

Section: Resultsmentioning

confidence: 99%

Endogenous opioids regulate moment-to-moment neuronal communication and excitability

et al. 2017

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“…Finally, an exciting new development is the identification of DOPr positive allosteric modulators (Burford et al, 2015). It is anticipated that major efforts will be made in the years to come to examine the potential of these novel types of DOPr ligands as therapeutic agents with reduced side effects.…”

Section: Mixed M-opioid Receptor Agonists/d-opioid Receptor Antagomentioning

confidence: 99%

Molecular Pharmacology ofδ-Opioid Receptors

et al. 2016

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“…At the level of the receptor, great progress is being made in the field of biased signalling, as well as the development of positive and negative modulators of receptor activity (see e.g. Kenakin, 2012; Khoury et al, 2014;Shukla et al, 2014;Bertekap et al, 2015;Bisignano et al, 2015;Burford et al, 2015). There is also significant potential for RGS proteins to serve a similar signalling pathway-specific role at the level of the G protein in order to improve the selectivity and efficacy of GPCR-targeted approaches.…”

Section: Why Target Rgs Proteins In Drug Discovery?mentioning

confidence: 99%

The evolution of regulators of G protein signalling proteins as drug targets – 20 years in the making: IUPHAR Review 21

Sjögren

2017

British J Pharmacology

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Regulators of G protein signalling (RGS) proteins are celebrating the 20th anniversary of their discovery. The unveiling of this new family of negative regulators of G protein signalling in the mid-1990s solved a persistent conundrum in the G protein signalling field, in which the rate of deactivation of signalling cascades in vivo could not be replicated in exogenous systems. Since then, there has been tremendous advancement in the knowledge of RGS protein structure, function, regulation and their role as novel drug targets. RGS proteins play an important modulatory role through their GTPase-activating protein (GAP) activity at active, GTP-bound Gα subunits of heterotrimeric G proteins. They also possess many non-canonical functions not related to G protein signalling. Here, an update on the status of RGS proteins as drug targets is provided, highlighting advances that have led to the inclusion of RGS proteins in the IUPHAR/BPS Guide to PHARMACOLOGY database of drug targets.Abbreviations DEP, Disheveled Egl-10 Pleckstrin; GAP, GTPase-activating protein; GGL, G protein γ-like; PPI, protein-protein interaction; RGS, regulator of G protein signalling; R7BP, R7 binding protein; R9AP, RGS9 associated protein IntroductionG protein-mediated signalling pathways have played a pivotal role in drug discovery and development for many decades. The large family of GPCRs or their downstream effectors are the target of 40% of clinically used drugs and thus represent a multi-billion-dollar industry (Wise et al., 2002). Interestingly, of the more than 300 non-olfactory GPCRs known, only a fraction of them are targeted by drugs. Thus, there is a large untapped area of drug development still available. Moreover, many GPCR drugs are associated with low efficacy and/or side effects. More targeted therapies are therefore required, and as we learn more about the structure and function of GPCRs and their regulators, these goals will be achievable.All biological signals are tightly regulated and for every on-switch there is usually an off-switch. GPCRs are activated by ligands, transmitting signalling information to Gα subunits of heterotrimeric G proteins by enhancing the exchange of GDP for GTP in the Gα nucleotide binding site, which results in the dissociation of Gα from Gβγ dimers and activation of both G protein components. Deactivation of G proteins does not occur by simple reversal of nucleotide exchange, but rather by an independently regulated GTPase activity, hydrolyzing GTP to GDP. Although Gα proteins possess an intrinsic ability to hydrolyze GTP, this process is very slow and cannot account for the transient nature of intracellular signalling cascades in vivo. Hence, additional kinetic mechanisms are required for the physiological timing of signals. One of the most critical of these kinetic mechanisms is mediated through regulator of G protein signalling (RGS) proteins, which have received increasing interest as novel drug targets in the past two decades. As a result, RGS proteins have now been added as the most recent ad...

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Discovery, Synthesis, and Molecular Pharmacology of Selective Positive Allosteric Modulators of the δ-Opioid Receptor

Cited by 55 publications

References 34 publications

Endogenous opioids regulate moment-to-moment neuronal communication and excitability

Endogenous opioids regulate moment-to-moment neuronal communication and excitability

Molecular Pharmacology ofδ-Opioid Receptors

The evolution of regulators of G protein signalling proteins as drug targets – 20 years in the making: IUPHAR Review 21

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