Sigma receptors are protein chaperones with the unexpected characteristic of being activated by ligand binding. As such, they represent intriguing new targets for potential drug development. As a protein chaperone, these "receptors" escort proteins from the endoplasmic reticulum to their destinations and act to correct misfolded proteins. The two subtypes of sigma receptors, named σ1 and σ2, are markedly distinct from each other. Agonists and antagonists at these receptors show promise as new drug targets, addressing a range of diseases including neurodegenerative disorders, cancer, and cardiac disorders, and may also be analgesic agents and rehabilitation drugs for opioid use disorder. As an analgesic, sigma receptors seem to be more effective in treating neuropathic than nociceptive pain. New bifunctional compounds are being developed with opioids, because agents targeting sigma receptors may have an opioid-sparing effect. The pipeline of agents based on the sigma receptors is long and may treat things from Fragile X syndrome to Parkinson's disease to Huntington's disease to cancer. A novel agent ADV502 acts as a high-affinity σ1 antagonist and partial agonist at the µ-opioid receptor and may be an important agent both for the treatment of neuropathic cancer pain and for rehabilitation of opioid use disorder. Since there has been little recent innovation in pain medicine regarding new compounds and drug targets, drugs that affect the sigma receptor system seem promising and encouraging.

01 Jan 2023·Acta Pharmaceutica Sinica B

Bispecific sigma-1 receptor antagonism and mu-opioid receptor partial agonism: WLB-73502, an analgesic with improved efficacy and safety profile compared to strong opioids

Article

Author: Pascual, Rosalía ; Merlos, Manuel ; Encina, Gregorio ; Monroy, Xavier ; Aubel, Bertrand ; Ayet, Eva ; García, Mónica ; Vidal-Torres, Alba ; Serafini, Maria Teresa ; Zamanillo, Daniel ; Vela, José Miguel ; Cabot, Anna ; Almansa, Carmen ; Romero, Luz ; Burgueño, Javier ; Codony, Xavier ; Fernández-Pastor, Begoña

Opioids are the most effective painkillers, but their benefit-risk balance often hinder their therapeutic use. WLB-73502 is a dual, bispecific compound that binds sigma-1 (S1R) and mu-opioid (MOR) receptors. WLB-73502 is an antagonist at the S1R. It behaved as a partial MOR agonist at the G-protein pathway and produced no/unsignificant β-arrestin-2 recruitment, thus demonstrating low intrinsic efficacy on MOR at both signalling pathways. Despite its partial MOR agonism, WLB-73502 exerted full antinociceptive efficacy, with potency superior to morphine and similar to oxycodone against nociceptive, inflammatory and osteoarthritis pain, and superior to both morphine and oxycodone against neuropathic pain. WLB-73502 crosses the blood-brain barrier and binds brain S1R and MOR to an extent consistent with its antinociceptive effect. Contrary to morphine and oxycodone, tolerance to its antinociceptive effect did not develop after repeated 4-week administration. Also, contrary to opioid comparators, WLB-73502 did not inhibit gastrointestinal transit or respiratory function in rats at doses inducing full efficacy, and it was devoid of proemetic effect (retching and vomiting) in ferrets at potentially effective doses. WLB-73502 benefits from its bivalent S1R antagonist and partial MOR agonist nature to provide an improved antinociceptive and safety profile respect to strong opioid therapy.

04 May 2021·XenobioticaQ4 · MEDICINE

Preliminary in vitro approach to evaluate the drug-drug interaction potential of EST73502, a dual µ-opioid receptor partial agonist and σ1 receptor antagonist

Q4 · MEDICINE

Article

Author: Balada, Ariadna ; Pretel, María José ; Serafini, Maria Teresa ; Ayet, Eva ; Reinoso, Raquel F. ; Yeste, Sandra

The potential for drug-drug interactions (DDI) of EST73502 was preliminary explored in vitro. EST73502 is a new chemical entity intended for oral pain treatment with dual sigma-1 receptor (σ₁R) antagonism and μ-opioid receptor (MOR) partial agonism, that presents a promising potent analgesic activity.Several enzymes were involved in EST73502 metabolism catalysing the formation of different metabolites, CYP3A4 and CYP2D6 being the main ones.Fraction unbound was determined due to its impact in interactions, a considerable proportion of EST73502 being available.EST73502 showed a low potential for CYP inhibition, except for CYP2D6 that showed time-dependent inhibition.No induction potential was found for CYP1A2 and 3A4, while CYP2B6 was induced at high concentration.EST73502 seemed to be a potential efflux transporter substrate (efflux ratio ≥ 2) but a negligible in vivo impact would be expected due to its high solubility and permeability in Caco-2 cells. P-gp inhibition was observed while no BCRP inhibition was detected.Preliminary in vitro interaction studies suggested that neither CYPs nor efflux transporters interactions would preclude further development of EST73502 to thoroughly assess the clinical relevance of these findings.

100 Deals associated with EST73502

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Cancer Pain	Phase 1	United States	Advantx Pharmaceuticals	28 Jul 2023
Cancer Pain	Phase 1	United States	NEMA Research, Inc.	28 Jul 2023
Opioid-Related Disorders	Phase 1	United States	NEMA Research, Inc.	28 Jul 2023
Opioid-Related Disorders	Phase 1	United States	Advantx Pharmaceuticals	28 Jul 2023
Pain	Preclinical	Spain	Esteve Pharmaceuticals SA	16 Oct 2020
Pain	Preclinical	Spain	Enantia	16 Oct 2020
Pain	Preclinical	Spain	WeLab Barcelona	16 Oct 2020

Clinical Result

Indication

Phase

Evaluation

View All Results

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis


No Data