Analysis of natural product regulation of opioid receptors in the treatment of human disease

S. Badal, Sophie Turfus, R. Rajnarayanan, C. Wilson-clarke, S.L. Sandiford

Research output: Contribution to journalReview article

2 Citations (Scopus)

Abstract

Opioid receptors (ORs), μOR, δOR, κOR and ORL1 mediate numerous signalling cascades, most importantly, through the modulation of ion channels. Research demonstrates the role of OR mediated signal transduction in treating pain, cancer, neurodegenerative disorders and cardiac insults. Yet, the primary application of drugs that modulate ORs is analgesia. Current opioids like morphine that are mainly μOR orthosteric agonists attract many undesirable side-effects (constipation, urinary retention, respiratory depression and hypotension) and the existing modus operandi against these is the inclusion of a μOR antagonist (for example, naloxone) which itself produces side-effects. As such, there is a current thrust to delineate the anti-nociceptive pathways mediated by ORs from the pathways involved in their induction of debilitating side-effects, in order to develop enhanced lead molecules. This review discusses the effects of natural products on the OR-induced signalling cascades and compares these to current synthetic leads and drugs. Important to these discussions is the complexity of OR signalling which involves OR trafficking, de- and re-sensitization, homo- and hetero-dimerization, the type of ligand binding (agonist, antagonist, reverse antagonist, orthosteric and allosteric agonist and antagonist in the context of biased agonism) and reasons for dysregulation that primarily occur because of inter-individual variations. Our current understanding of the different forms of ORs has expanded, thus introducing the concept of allosterism, which is also discussed. The authors present possible combination therapies to be explored towards developing the ‘Holy Grail’ of analgesics, for example, ignavine, the natural μOR positive allosteric modulator (PAM) with codeine and the natural fascaplysin, a balanced agonist with fentanyl. There remain many gaps in natural products research on ORs, more so on ORL1 and δ- and κ receptors. Furthermore, additional exploration of ORs' modulation is needed for ameliorating other associated disease conditions of global concern.
LanguageEnglish
Pages51-80
Number of pages30
JournalPharmacology and Therapeutics
Volume184
Early online date31 Oct 2017
DOIs
Publication statusPublished - 1 Apr 2018
Externally publishedYes

Fingerprint

Opioid Receptors
Biological Products
Therapeutics
Dimerization
Codeine
Nimodipine
kappa Opioid Receptor
delta Opioid Receptor
Urinary Retention
Fentanyl
Constipation
Naloxone
Ion Channels
Research
Respiratory Insufficiency
Neurodegenerative Diseases
Pharmaceutical Preparations
Hypotension
Analgesia
Morphine

Cite this

Badal, S. ; Turfus, Sophie ; Rajnarayanan, R. ; Wilson-clarke, C. ; Sandiford, S.L. / Analysis of natural product regulation of opioid receptors in the treatment of human disease. In: Pharmacology and Therapeutics. 2018 ; Vol. 184. pp. 51-80.
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Analysis of natural product regulation of opioid receptors in the treatment of human disease. / Badal, S.; Turfus, Sophie; Rajnarayanan, R.; Wilson-clarke, C.; Sandiford, S.L.

In: Pharmacology and Therapeutics, Vol. 184, 01.04.2018, p. 51-80.

Research output: Contribution to journalReview article

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T1 - Analysis of natural product regulation of opioid receptors in the treatment of human disease

AU - Badal, S.

AU - Turfus, Sophie

AU - Rajnarayanan, R.

AU - Wilson-clarke, C.

AU - Sandiford, S.L.

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AB - Opioid receptors (ORs), μOR, δOR, κOR and ORL1 mediate numerous signalling cascades, most importantly, through the modulation of ion channels. Research demonstrates the role of OR mediated signal transduction in treating pain, cancer, neurodegenerative disorders and cardiac insults. Yet, the primary application of drugs that modulate ORs is analgesia. Current opioids like morphine that are mainly μOR orthosteric agonists attract many undesirable side-effects (constipation, urinary retention, respiratory depression and hypotension) and the existing modus operandi against these is the inclusion of a μOR antagonist (for example, naloxone) which itself produces side-effects. As such, there is a current thrust to delineate the anti-nociceptive pathways mediated by ORs from the pathways involved in their induction of debilitating side-effects, in order to develop enhanced lead molecules. This review discusses the effects of natural products on the OR-induced signalling cascades and compares these to current synthetic leads and drugs. Important to these discussions is the complexity of OR signalling which involves OR trafficking, de- and re-sensitization, homo- and hetero-dimerization, the type of ligand binding (agonist, antagonist, reverse antagonist, orthosteric and allosteric agonist and antagonist in the context of biased agonism) and reasons for dysregulation that primarily occur because of inter-individual variations. Our current understanding of the different forms of ORs has expanded, thus introducing the concept of allosterism, which is also discussed. The authors present possible combination therapies to be explored towards developing the ‘Holy Grail’ of analgesics, for example, ignavine, the natural μOR positive allosteric modulator (PAM) with codeine and the natural fascaplysin, a balanced agonist with fentanyl. There remain many gaps in natural products research on ORs, more so on ORL1 and δ- and κ receptors. Furthermore, additional exploration of ORs' modulation is needed for ameliorating other associated disease conditions of global concern.

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KW - Drug dependence/addiction

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KW - G proteins

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