Discovery of Novel Delta Opioid Receptor (DOR) Inverse Agonist and Irreversible (Non-Competitive) Antagonists

The delta opioid receptor (DOR) is a crucial receptor system that regulates pain, mood, anxiety, and similar mental states. DOR agonists, such as SNC80, and DOR-neutral antagonists, such as naltrindole, have been developed to investigate the DOR in vivo and as potential therapeutics for pain and depression. However, few inverse agonists and non-competitive/irreversible antagonists have been developed, and none are widely available. This leaves a gap in our pharmacological toolbox and limits our ability to investigate the biology of this receptor. Thus, we designed and synthesized the novel compounds SRI-9342 as an irreversible antagonist and SRI-45127/SRI-45128 as inverse agonists. Then, these compounds were evaluated in vitro for their binding affinity by radioligand binding and functional activity by 35S-GTPγS coupling and cAMP accumulation in cells expressing the human DOR. All three compounds demonstrated high binding affinity and selectivity at the DOR, and all three displayed their hypothesized molecular pharmacology of irreversible antagonism (SRI-9342) or inverse agonism (SRI-45127/SRI-45128). Together, these results demonstrate that we have designed new inverse agonists and irreversible antagonists of the DOR based on a novel chemical scaffold. These new compounds will provide new tools to investigate the biology of the DOR or even new potential therapeutics.

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Chemical Characterization and in vitro Metabolism of a Novel Class of Delta Opioid Receptor Agonists, Analogs of SNC-80

ChemistrySelect ◽

10.1002/slct.201803906 ◽

2019 ◽

Vol 4 (7) ◽

pp. 2109-2115

Author(s):

Elisabetta Maria Usai ◽

Ilaria Manca ◽

Francesca Pettinau ◽

Antonio Mastino ◽

Barbara Pittau

Keyword(s):

Opioid Receptor ◽

Chemical Characterization ◽

In Vitro Metabolism ◽

Delta Opioid Receptor ◽

Receptor Agonists ◽

Opioid Receptor Agonists

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Some cannabinoid receptor ligands and their distomers are direct-acting openers of SUR1 KATP channels

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00250.2011 ◽

2012 ◽

Vol 302 (5) ◽

pp. E540-E551 ◽

Cited By ~ 9

Author(s):

Christopher J. Lynch ◽

Qing Zhou ◽

Show-Ling Shyng ◽

David J. Heal ◽

Sharon C. Cheetham ◽

...

Keyword(s):

Chronic Treatment ◽

Cannabinoid Receptor ◽

Radioligand Binding ◽

In Vitro Studies ◽

Zucker Rats ◽

K Channel ◽

Inverse Agonists ◽

Chronic Effects

Here, we examined the chronic effects of two cannabinoid receptor-1 (CB1) inverse agonists, rimonabant and ibipinabant, in hyperinsulinemic Zucker rats to determine their chronic effects on insulinemia. Rimonabant and ibipinabant (10 mg·kg−1·day−1) elicited body weight-independent improvements in insulinemia and glycemia during 10 wk of chronic treatment. To elucidate the mechanism of insulin lowering, acute in vivo and in vitro studies were then performed. Surprisingly, chronic treatment was not required for insulin lowering. In acute in vivo and in vitro studies, the CB1 inverse agonists exhibited acute K channel opener (KCO; e.g., diazoxide and NN414)-like effects on glucose tolerance and glucose-stimulated insulin secretion (GSIS) with approximately fivefold better potency than diazoxide. Followup studies implied that these effects were inconsistent with a CB1-mediated mechanism. Thus effects of several CB1 agonists, inverse agonists, and distomers during GTTs or GSIS studies using perifused rat islets were unpredictable from their known CB1 activities. In vivo rimonabant and ibipinabant caused glucose intolerance in CB1 but not SUR1-KO mice. Electrophysiological studies indicated that, compared with diazoxide, 3 μM rimonabant and ibipinabant are partial agonists for K channel opening. Partial agonism was consistent with data from radioligand binding assays designed to detect SUR1 KATP KCOs where rimonabant and ibipinabant allosterically regulated 3H-glibenclamide-specific binding in the presence of MgATP, as did diazoxide and NN414. Our findings indicate that some CB1 ligands may directly bind and allosterically regulate Kir6.2/SUR1 KATP channels like other KCOs. This mechanism appears to be compatible with and may contribute to their acute and chronic effects on GSIS and insulinemia.

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In vitro exposure to peptidic delta opioid receptor antagonists results in limited immunosuppression

Neuropeptides ◽

10.1016/s0143-4179(97)90026-3 ◽

1997 ◽

Vol 31 (1) ◽

pp. 89-93 ◽

Cited By ~ 5

Author(s):

R.V House ◽

P.T Thomas ◽

H.N Bhargava

Keyword(s):

Opioid Receptor ◽

Delta Opioid Receptor ◽

Receptor Antagonists ◽

Opioid Receptor Antagonists ◽

In Vitro Exposure

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0155 SUVN-G3031, A Potent and Selective Histamine H3 Receptor Inverse Agonist - Differentiating Features Over Current Treatments of Narcolepsy

SLEEP ◽

10.1093/sleep/zsaa056.153 ◽

2020 ◽

Vol 43 (Supplement_1) ◽

pp. A61-A61

Author(s):

A Shinde ◽

R Subramanian ◽

R Palacharla ◽

S Pandey ◽

V Benade ◽

...

Keyword(s):

Binding Affinity ◽

Abuse Liability ◽

Species Variation ◽

Pharmacological Agents ◽

Histamine H3 Receptor ◽

Inverse Agonists ◽

H3 Receptor ◽

Histamine H3

Abstract Introduction Majority of pharmacological agents used in the treatment of narcolepsy have several limitations. Both nonclinical and clinical evidences suggest usefulness of the histamine H3 receptor (H3R) inverse agonists for the treatment of narcolepsy and addressing several of the current limitations. Methods Extensive nonclinical studies were carried out for SUVN-G3031 and other pharmacological agents that are currently being used for the treatment of narcolepsy. Nonclinical parameters like inter-species binding affinity, selectivity profile, in vivo and in vitro ADME features, nonclinical efficacy, neurochemistry and safety were compared. Results SUVN-G3031 has no inter-species variation in binding affinity at H3R with less than 50% inhibition at 1 µM against 70 other targets. Unlike pitolisant, SUVN-G3031 has no significant binding affinity at sigma 1 and 2 receptor. SUVN-G3031 has no inhibition and induction liability towards major CYP enzymes and transporters. Pitolisant is reported to be a CYP3A4, CYP2B6, and CYP1A2 inducer and a CYP2D6 and OCT1 inhibitor. SUVN-G3031 has robust wake promoting effects. SUVN-G3031 showed negligible affinity towards hERG channel with IC50 > 10 µM and had no effects on any ECG parameters in dog telemetry study. SUVN-G3031 did not show convulsion in rats up to the tested dose of 100 mg/kg, p.o. Most of the pharmacological agents used for the treatment of narcolepsy have abuse liability; SUVN-G3031 produced no change in the striatal and accumbal dopamine levels in rats suggesting no propensity to induce abuse liability. Unlike competing H3R inverse agonists, SUVN-G3031 has no effects on fertility and embryo-fetal development up to the highest tested doses. Conclusion Nonclinical studies demonstrate superiority of SUVN-G3031 over pharmacological agents currently used in the treatment of narcolepsy. SUVN-G3031 is being evaluated in a Phase 2 study as monotherapy for the treatment of narcolepsy with and without cataplexy (ClinicalTrials.gov Identifier: NCT04072380). Support None

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