Simultaneous Targeting of Multiple Opioid Receptors
Simultaneous Targeting of Multiple Opioid Receptors
Opioid receptors are currently classified as µ (mu: mOP), δ (delta: dOP), κ (kappa: kOP) with a fourth related non-classical opioid receptor for nociceptin/orphainin FQ, NOP. Morphine is the current gold standard analgesic acting at MOP receptors but produces a range of variably troublesome side-effects, in particular tolerance. There is now good laboratory evidence to suggest that blocking DOP while activating MOP produces analgesia (or antinociception) without the development of tolerance. Simultaneous targeting of MOP and DOP can be accomplished by: (i) co-administering two selective drugs, (ii) administering one non-selective drug,or (iii) designing a single drug that specifically targets both receptors; a bivalent ligand. Bivalent ligands generally contain two active centres or pharmacophores that are variably separated by a chemical spacer and there are several interesting examples in the literature. For example linking the MOP agonist oxymorphone to the DOP antagonist naltrindole produces a MOP/DOP bivalent ligand that should produce analgesia with reduced tolerance.The type of response/selectivity produced depends on the pharmacophore combination (e.g. oxymorphone and naltrindole as above) and the space between them. Production and evaluation of bivalent ligands is an emerging field in drug design and for anaesthesia, analgesics that are designed not to be highly selective morphine-like(MOP) ligands represents a new avenue for the production of useful drugs for chronic (and in particular cancer) pain.
Acute pain is a very common presenting complaint in primary and secondary care. Chronic pain, on the other hand, is a rather complex symptom associated with a range of diseases and is particularly difficult to treat effectively. Chronic pain is one of the most common symptoms associated with cancer, with a prevalence of approximately 30–50% among patients who are undergoing active treatment for a solid tumour and 70–90% among those with advanced disease. Records show that 88% of cancer patients in the last year of their life are in pain and 47% of those treated for pain by their general practitioner said their treatment only partially controlled their pain. From this description of chronic cancer pain it is fair to state that, despite a derange of potential therapeutic targets, the control of cancer pain is poor.
Current classification of opioids and their receptors (MOP;µ, DOP; δ, and KOP; κ) is summarized in Table 1 , where it is worthy of note that the main target for analgesia is the MOP receptor. Indeed, in an elegant study by Kieffer and colleagues, mice in which the MOP gene was deleted did not display morphine-induced analgesia. A fourth receptor was identified by cloning, which was abbreviated as NOP, while the identification of its endogenous peptide followed shortly, named nociceptin/orphanin FQ or N/OFQ. The structure of the NOP receptor and the transduction pathways after its activation show that it has been evolved from the opioid receptor family. Selective ligands have been synthesized for the NOP receptor, that is J-113397 and UFP-101. Pharmacologically this is not a classical opioid receptor, as non-selective opioid antagonists (i.e. naloxone) display negligible affinity. The International Union of (basic and clinical) Pharmacology (IUPHAR) database of receptors proposes that the NOP receptor is considered as a non-opioid branch of the opioid receptor family.
Opioids are the gold standard for acute pain and are often used with some effect in chronic cancer pain. However, there is a trade-off between good analgesia and poor side-effect profile. Indeed, tolerance to opioids (morphine) develops such that dose escalation is required which increases the prevalence and severity of side-effects. There is a need for morphine-like molecules with reduced side-effects such as (i) tolerance liability, (ii) depressed respiration, and (iii) reduced gastrointestinal motility.
In 1994 in an editorial in this journal we stated that "As far as clinical anaesthetists are concerned, the "holy grail" of profound analgesia without significant side-effects has yet to be realized". While there have been significant advances in that time, the "holy grail" remains unrealized. In that editorial we also suggested that highly selective MOP receptor agonists were the future for modern analgesics. Using the vast amount of post-cloning pharmacology data now available we question the wisdom of developing more morphine-like analgesics and explore the properties of low-selectivity mixed opioid molecules (multi-targeting) in the hope that these may produce new drug prototypes to address clinical need in chronic pain.
Abstract and Introduction
Abstract
Opioid receptors are currently classified as µ (mu: mOP), δ (delta: dOP), κ (kappa: kOP) with a fourth related non-classical opioid receptor for nociceptin/orphainin FQ, NOP. Morphine is the current gold standard analgesic acting at MOP receptors but produces a range of variably troublesome side-effects, in particular tolerance. There is now good laboratory evidence to suggest that blocking DOP while activating MOP produces analgesia (or antinociception) without the development of tolerance. Simultaneous targeting of MOP and DOP can be accomplished by: (i) co-administering two selective drugs, (ii) administering one non-selective drug,or (iii) designing a single drug that specifically targets both receptors; a bivalent ligand. Bivalent ligands generally contain two active centres or pharmacophores that are variably separated by a chemical spacer and there are several interesting examples in the literature. For example linking the MOP agonist oxymorphone to the DOP antagonist naltrindole produces a MOP/DOP bivalent ligand that should produce analgesia with reduced tolerance.The type of response/selectivity produced depends on the pharmacophore combination (e.g. oxymorphone and naltrindole as above) and the space between them. Production and evaluation of bivalent ligands is an emerging field in drug design and for anaesthesia, analgesics that are designed not to be highly selective morphine-like(MOP) ligands represents a new avenue for the production of useful drugs for chronic (and in particular cancer) pain.
Introduction
Acute pain is a very common presenting complaint in primary and secondary care. Chronic pain, on the other hand, is a rather complex symptom associated with a range of diseases and is particularly difficult to treat effectively. Chronic pain is one of the most common symptoms associated with cancer, with a prevalence of approximately 30–50% among patients who are undergoing active treatment for a solid tumour and 70–90% among those with advanced disease. Records show that 88% of cancer patients in the last year of their life are in pain and 47% of those treated for pain by their general practitioner said their treatment only partially controlled their pain. From this description of chronic cancer pain it is fair to state that, despite a derange of potential therapeutic targets, the control of cancer pain is poor.
Current classification of opioids and their receptors (MOP;µ, DOP; δ, and KOP; κ) is summarized in Table 1 , where it is worthy of note that the main target for analgesia is the MOP receptor. Indeed, in an elegant study by Kieffer and colleagues, mice in which the MOP gene was deleted did not display morphine-induced analgesia. A fourth receptor was identified by cloning, which was abbreviated as NOP, while the identification of its endogenous peptide followed shortly, named nociceptin/orphanin FQ or N/OFQ. The structure of the NOP receptor and the transduction pathways after its activation show that it has been evolved from the opioid receptor family. Selective ligands have been synthesized for the NOP receptor, that is J-113397 and UFP-101. Pharmacologically this is not a classical opioid receptor, as non-selective opioid antagonists (i.e. naloxone) display negligible affinity. The International Union of (basic and clinical) Pharmacology (IUPHAR) database of receptors proposes that the NOP receptor is considered as a non-opioid branch of the opioid receptor family.
Opioids are the gold standard for acute pain and are often used with some effect in chronic cancer pain. However, there is a trade-off between good analgesia and poor side-effect profile. Indeed, tolerance to opioids (morphine) develops such that dose escalation is required which increases the prevalence and severity of side-effects. There is a need for morphine-like molecules with reduced side-effects such as (i) tolerance liability, (ii) depressed respiration, and (iii) reduced gastrointestinal motility.
In 1994 in an editorial in this journal we stated that "As far as clinical anaesthetists are concerned, the "holy grail" of profound analgesia without significant side-effects has yet to be realized". While there have been significant advances in that time, the "holy grail" remains unrealized. In that editorial we also suggested that highly selective MOP receptor agonists were the future for modern analgesics. Using the vast amount of post-cloning pharmacology data now available we question the wisdom of developing more morphine-like analgesics and explore the properties of low-selectivity mixed opioid molecules (multi-targeting) in the hope that these may produce new drug prototypes to address clinical need in chronic pain.
Source...