BJA Advance Access published online on May 27, 2009
British Journal of Anaesthesia, doi:10.1093/bja/aep129
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Simultaneous targeting of multiple opioid receptors: a strategy to improve side-effect profile
1 Department of Cardiovascular Sciences (Pharmacology and Therapeutics Group), Division of Anaesthesia, Critical Care and Pain Management
2 Department of Health Sciences, Division of Anaesthesia, Critical Care and Pain Management, University of Leicester, Leicester Royal Infirmary, Leicester LE1 5WW, UK
3 Department of Pharmaceutical Sciences
4 Department of Experimental and Clinical Medicine, Section of Pharmacology, University of Ferrara, 44100 Ferrara, Italy
* Corresponding author. E-mail: DGL3{at}le.ac.uk
Opioid receptors are currently classified as µ (mu: mOP), 
(delta: dOP), 
(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.
Keywords: analgesics, opioid; cancer; pharmacology, opioids; receptors, opioid; structure, molecular
R.G., S.S. and G.C. are founders of a university spin-out company, University of Ferrara Peptides (UFP), that is involved in the development of opioid ligands. N.D., D.J.R., and D.G.L. are collaborators with UFP.