Opioid ligands with mixed μ/δ opioid receptor interactions: An emerging approach to novel analgesics

Abstract

A BSTRACTOpioids are widely used in the treatment of severe pain. The clinical use of the opioids is limited by serious side effects such as respiratory depression, constipation, development of tolerance, and physical dependence and addiction liabilities. Most of the currently available opioid analgesics exert their analgesic and adverse effects primarily through the opioid receptors. A large number of biochemical and pharmacological studies and studies using genetically modifi ed animals have provided convincing evidence regarding the existence of modulatory interactions between opioid and ␦ receptors. Several studies indicate that ␦ receptor agonists as well as ␦ receptor antagonists can provide benefi cial modulation to the pharmacological effects of agonists. For example, ␦ agonists can enhance the analgesic potency and effi cacy of agonists, and ␦ antagonists can prevent or diminish the development of tolerance and physical dependence by agonists. On the basis of these observations, the development of new opioid ligands possessing mixed agonist/ ␦ agonist profi le and mixed agonist/ ␦ antagonist profi le has emerged as a promising new approach to analgesic drug development. A brief overview of -␦ interactions and recent developments in identifi cation of ligands possessing mixed agonist/ ␦ agonist and agonist/ ␦ antagonist activities is provided in this report. K EYWORDS:Analgesics , Opioid Ligands , Mixed Mu/Delta agonists , Mixed Mu agonist/Delta antagonists , Peptides , Nonpeptides INTRODUCTIONOpioid analgesics are the standard therapeutic agents for the treatment of moderate-to-severe pain. These drugs exert their analgesic activity through their interaction with the opioid , ␦ , or receptors as agonists. The clinical usefulness of opioid agonists such as morphine, however, is limited by signifi cant side effects such as respiratory depression, constipation, development of tolerance and physical dependence, and addiction potential. One approach to limit -receptor-mediated side effects is to selectively target ␦ and opioid receptors. This approach has been explored using agonist ligands selective for ␦ and opioid receptors but has seen only limited success. The ␦ agonists generally display limited analgesic effi cacy and receptor agonists are limited to their use as peripheral analgesics owing to their psychotomimetic and dysphoric central effects. An alternative approach that is gaining considerable interest is the development of compounds that possess mixed opioid activity at the different opioid receptors. 1 , 2 Several lines of evidence indicate the existence of physical and functional interactions between the opioid receptors, particularly between the and ␦ receptors. Several biochemical and pharmacological studies using and ␦ receptor ligands gave an early indication of such interactions between the and ␦ receptors. [3][4][5][6] The and ␦ opioid receptors exist on overlapping populations of neurons in painmodulating regions of the central nervous system, and the presence of both and ␦ receptors ...

[6,7]‐Heterocycle‐Fused 14‐Hydroxymorphinan Derivatives: Design, Synthesis, and Opioid Receptor Activity

“…As has been reported [8][9][10][11][12][27][28][29] by several research groups, including ours, that k agonists with m partial agonistic or antagonistic activities are more efficacious than the pure k agonists in treating several CNS disorders, especially drug abuse, several compounds in our current studies, such as thiazole 8 and imidazo[2,1-b]thiazoles 10 and 11, which have agonistic activity at the k and partial agonistic or antagonistic activities at m receptors, are worthy of further investigation.…”

Strategy for making safer opioids bolstered

“…These include the development of partial activators of the µOR (ref. 4); of compounds that activate the µOR but block other opioidreceptor subtypes 5 ; and of compounds that are restricted to the peripheral, rather than the central, nervous system 6 . Other approaches have involved molecules that bind to the µOR only in acidic environments 7 (which are often associated with damaged tissue), and compounds that target opioid receptors formed from more than one subtype 8 .…”

“…More than 150 estimates of equilibrium climate sensitivity (ECS) have been published 3 , many of which suggest that worryingly high sensitivities are possible -including one that was published in Nature just a few weeks ago 4 . On page 319, Cox et al 5 use an ingenious approach to rule out high estimates. If correct, this would improve the chances of achieving internationally agreed targets for minimizing global warming.…”

“…The estimate 1 from the Intergovernmental Panel on Climate Change (IPCC) published in 2013 is based on several lines of evidence. Cox et al 5 now report estimates based on an analysis of surfacetemperature variation predicted by climate models. Their analysis rules out high estimates of ECS.…”

5′-Halogenated analogs of oxymorphindole

“…7 Ananthan extended these studies to a non-peptidic dual profile ligand 2, but the results are difficult to interpret due to low mu opioid agonist efficacy and potency, and the need to administer the drug icv. 6,8 As part of our studies into developing non-peptide ligands with a dual profile of potent mu opioid agonism and delta opioid antagonism as potential analgesics lacking tolerance and dependence, we previously reported that the presence of a 6,7-fused indolic group does not necessarily result in delta opioid selectivity. 9 This is in contrast to accepted structure-activity relationships, where the indole is considered responsible for delta selectivity.…”