Strategies towards safer opioid analgesics—A review of old and upcoming targets

Este es un archivo PDF de un manuscrito inédito que ha sido aceptado para su publicación en la Revista de la Sociedad Española Multidisciplinar del Dolor. Como un servicio a nuestros clientes estamos proporcionando esta primera versión del manuscrito en estado de prepublicación. El manuscrito será sometido a la corrección de estilo final, composición y revisión de la prueba resultante antes de que se publique en su forma final. Tenga en cuenta que durante el proceso de producción se pueden dar errores, lo que podría afectar el contenido final. El copyright y todos los derechos legales que se aplican al artículo pertenecen a la

show abstract

“…Un receptor puede, por tanto, estar funcionado de forma independiente, como homodimero o como heterodímero (13).…”

Section: Receptores Opioides Heterodímerosunclassified

Nuevas estrategias y generaciones de analgésicos opioides: ¿qué se está investigando?

Regueras¹,

Torres²,

Velazquez³

2022

MPJ

View full text Add to dashboard Cite

show abstract

“…However, given pre-clinical and clinical results, biased agonists can represent a useful step in research strategy for the development of safer opioid analgesics. In this context, also dual agonism shown by selected molecules acting as MOR/NOP receptor agonists (e.g., BU08028, BU10038, and AT-121) as well as MOR/KOR agonists, KOR/ DOR agonists, and MOR agonists/KOR antag-onists could be considered a promising approach in this field (71).…”

Section: Conclusion and Future Perspectivementioning

confidence: 99%

New pharmacological strategies for analgesic drug development: focus on biased m opioid receptor agonists

Rullo¹,

Losapio²,

Morosini³

et al. 2022

Pharm Adv

View full text Add to dashboard Cite

Chronic pain affects more than 30% of people worldwide and although mortality rates are highest for other pathologies, it is one of the main sources of human suffering and disability that profoundly impacts patients' quality of life. To date, opioids still represent the reference treatment for moderate to severe chronic pain, however their use is strongly limited by a plethora of unwanted side effects including analgesic tolerance and opioid induced hyperalgesia. In the last few years, numerous efforts have been made in order to develop new analgesic drugs characterized by reduced side effects and by a safer pharmacological profile. Molecules capable of modulating different downstream pathways, known as biased agonists, are one proposed strategy for the treatment of chronic pain due to their suggested ability to discriminate between analgesic and adverse effect. In this review, we discuss the pharmacological outcomes of opioid biased ligands by bringing together cellular results and the available data from clinical trials; in particular, we focus on biased µ-opioid receptor agonists given their therapeutic relevance. Impact statementThe concept of MOR biased agonism has been used to identify new analgesic drugs. Although some criticism has been raised toward this strategy, it represents a useful step for the development of safer opioid analgesics.

show abstract

“…Recently, the simultaneous multiple opioid receptor (MOR, DOR or δ, kappa opioid receptor [KOR] or κ, and nociceptin-opioid receptor [NOP]) activation has been proposed to reduce the excessive MOR overstimulation and its related side effects. This strategy led to the development of several mixed opioid receptor agonist and mixed agonist–antagonist ligands capable of carrying out MOR–KOR agonism, MOR–NOP receptor agonism, MOP–DOR dual agonism, MOR agonism–DOR antagonism, and KOR–DOR agonism [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Current and Future Therapeutic Options in Pain Management: Multi-mechanistic Opioids Involving Both MOR and NOP Receptor Activation

Coluzzi

Rullo

Scerpa³

et al. 2022

CNS Drugs

View full text Add to dashboard Cite

Opioids are widely used in chronic pain management, despite major concerns about their risk of adverse events, particularly abuse, misuse, and respiratory depression from overdose. Multi-mechanistic opioids, such as tapentadol and buprenorphine, have been widely studied as a valid alternative to traditional opioids for their safer profile. Special interest was focused on the role of the nociceptin opioid peptide (NOP) receptor in terms of analgesia and improved tolerability. Nociceptin opioid peptide receptor agonists were shown to reinforce the antinociceptive effect of mu opioid receptor (MOR) agonists and modulate some of their adverse effects. Therefore, multi-mechanistic opioids involving both MOR and NOP receptor activation became a major field of pharmaceutical and clinical investigations. Buprenorphine was re-discovered in a new perspective, as an atypical analgesic and as a substitution therapy for opioid use disorders; and buprenorphine derivatives have been tested in animal models of nociceptive and neuropathic pain. Similarly, cebranopadol, a full MOR/NOP receptor agonist, has been clinically evaluated for its potent analgesic efficacy and better tolerability profile, compared with traditional opioids. This review overviews pharmacological mechanisms of the NOP receptor system, including its role in pain management and in the development of opioid tolerance. Clinical data on buprenorphine suggest its role as a safer alternative to traditional opioids, particularly in patients with non-cancer pain; while data on cebranopadol still require phase III study results to approve its introduction on the market. Other bifunctional MOR/NOP receptor ligands, such as BU08028, BU10038, and AT-121, are currently under pharmacological investigations and could represent promising analgesic agents for the future.

show abstract

Strategies towards safer opioid analgesics—A review of old and upcoming targets

Cited by 40 publications

References 151 publications

Nuevas estrategias y generaciones de analgésicos opioides: ¿qué se está investigando?

Nuevas estrategias y generaciones de analgésicos opioides: ¿qué se está investigando?

New pharmacological strategies for analgesic drug development: focus on biased m opioid receptor agonists

Current and Future Therapeutic Options in Pain Management: Multi-mechanistic Opioids Involving Both MOR and NOP Receptor Activation

Contact Info

Product

Resources

About