Chapter 2
Commentary on the Current State of Opioid-Related Research Downloaded by UNIV ILLINOIS URBANA on May 13, 2013 | http://pubs.acs.org Publication Date (Web): May 10, 2013 | doi: 10.1021/bk-2013-1131.ch002
John W. Lewis* Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK *E-mail:
[email protected]; Phone: 44(0)1225-383103; Fax: 44(0)1225-386114
Morphine has been the “gold standard” of clinical analgesics since its isolation from opium in the middle of the C19th. Though its unequivocal structure was not determined until 1925, the search for improvements lacking morphine’s principle side effects, dependence/tolerance and respiratory depression, has been continuous but not greatly successful. During the last nearly 50 years when I have been in, or close to the field, major advances in terms of the identification of three types of opioid receptor – mu (MOP), kappa (KOP) and delta (DOP) – and their cloning have been made. More recently (1994) the identification of a fourth “opioidlike” receptor and its natural ligand N/OFQ has given fresh impetus to discovery research programmes. These events are reflected in the balance of chapters in the current volume in which precedence is given to ligands having NOP activity and its potential to produce non-rewarding analgesics and substance abuse treatments. The major efforts by the pharmaceutical industry to exploit selective KOP and DOP agonists as “non-addicting” analgesics have not yielded much success, though butorphanol and nalbuphine, mixed MOP/KOP partial agonists have found limited clinical use. Interest in KOP agonists lacking CNS penetration as peripheral analgesics for the treatment of visceral pain continues as it does for DOP ligands in bifunctional opioids with MOP agonists. These aspects are covered in chapters in the current volume. An extremely useful timeline for the history of N/OFQ and selective peptide and non-peptide NOP agonists and antagonists is shown in Calo’s chapter, which is primarily concerned with peptide ligands for NOP. Though there is no chapter devoted to non-peptide NOP agonists and antagonists there are recent reviews of this topic and their structure – activity relationships and pharmacology are covered in this volume in the chapters of Zaveri, Toll, Whiteside and Ko. In the latter, the important differences between non-human primates and rodents in terms of supraspinal and systemic effects of NOP agonists are discussed. The agonists in © 2013 American Chemical Society In Research and Development of Opioid-Related Ligands; Ko, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2013.
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rodents are either pronociceptive (i.c.v.) or marginally active (s.c.) whereas by both spinal and systemic routes of administration in primates pronounced activity against thermal nociception, allodynia, and hyperalgesia was demonstrated. Thus the potential of NOP agonists as non-addictive analgesics can be recognised. However, recent focus has been on bifunctional MOP/NOP agonist ligands based on the hypothesis that since NOP agonists block the development of tolerance and dependence in morphine, ligands having both NOP and MOP agonism should maintain analgesic activity, but show less tolerance and addiction liability. Design strategies for the mixed agonist ligands have started from leads with MOP or NOP agonist selectivity, into which the alternative affinity/efficacy is grafted. The Zaveri and Toll chapters predominantly relate to series originating with NOP selectivity. They also refer to mixed ligands related to a lead with MOP (partial) agonist selectivity, buprenorphine, which was shown to have low efficacy, modest potency partial NOP agonist activity, as well as the established MOP partial agonism and KOP, DOP antagonism. With variable efficacy for all the opioid receptor types, the orvinols to which etorphine and diprenorphine as well as buprenorphine belong, have proved amenable to the introduction of NOP activity equal to, or superior to, that of buprenorphine. Discovery programmes with the aim of further improving NOP affinity and efficacy whilst retaining buprenorphine’s KOP antagonism in combination with either MOP partial agonism or MOP antagonism are discussed in the Husbands’ chapter. The use of methodone and buprenorphine as opioid abuse medications is comprehensively reviewed in Saxon’s chapter. Sufficient up to date information is provided to satisfy the needs of those entering the field. This subject is also covered in Comer’s chapter, which primarily addresses the abuse of MOP agonist analgesics, a serious problem as these opioids have become increasingly prescribed for chronic pain. In conclusion, this volume provides the reader with a picture of the state of opioid science in the second decade of the twenty first century. Clinical use of opioids as analgesics is still overwhelmingly confined to MOP agonists. The prospects for selective KOP and DOP agonists are not great but there is hope that NOP agonists, particularly in bifunctional alliance with MOP agonism, will eventually reach clinical practice as analgesics and possibly as substance abuse medications. Buprenorphine provides a lead for such developments.
6 In Research and Development of Opioid-Related Ligands; Ko, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2013.
