Mark F Bird1, David G Lambert. 1. University Department Cardiovascular Sciences, Division of Anaesthesia, Critical Care and Pain Management, RK-CSB, Leicester Royal Infirmary, Leicester LE2 7LX, UK.
Abstract
PURPOSE OF REVIEW: This article aims to discuss the multitarget concept for opioid receptor ligands framed on early observations that activating MOP (mu:μ) receptor whilst simultaneously blocking DOP (delta:δ) receptors reduces the onset of morphine tolerance. The review period is ostensibly calendar year 2014 but the new work in 2013 is also covered. RECENT FINDINGS: Two molecules of interest with MOP agonist/DOP agonist and MOP agonist/DOP antagonist profiles were described: Rv-Jim-C3 and 3-[(2R,6R,11R)-8-hydroxy-6,11-dimethyl-1,4,5,6-tetrahydro-2,6-methano-3-benzazocin-3(2H)-yl]-N-phenylpropanamide (LP1), respectively. Both were effective in neuropathic pain (wherein classical single target opioids have low efficacy) with the latter having a predicted reduced tolerance profile. BU0807 is a buprenorphine derivative with mixed MOP/NOP agonist activity and this was shown to be effective in abdominal pain. SR16435 and GRT6005 (cebranopadol) are mixed MOP/MOP agonists with varying degrees of partial agonism. Both displayed significant antinociceptive activity and reduced tolerance potential in preclinical models. SUMMARY: There is growing evidence for and interest in the design and evaluation of mixed opioids that extend beyond the MOP/DOP pairing to now include NOP. Indeed, a mixed MOP/NOP ligand is close to the clinic; this will reinvigorate the search for other mixed molecules with reduced side-effect profiles.
PURPOSE OF REVIEW: This article aims to discuss the multitarget concept for opioid receptor ligands framed on early observations that activating MOP (mu:μ) receptor whilst simultaneously blocking DOP (delta:δ) receptors reduces the onset of morphine tolerance. The review period is ostensibly calendar year 2014 but the new work in 2013 is also covered. RECENT FINDINGS: Two molecules of interest with MOP agonist/DOP agonist and MOP agonist/DOP antagonist profiles were described: Rv-Jim-C3 and 3-[(2R,6R,11R)-8-hydroxy-6,11-dimethyl-1,4,5,6-tetrahydro-2,6-methano-3-benzazocin-3(2H)-yl]-N-phenylpropanamide (LP1), respectively. Both were effective in neuropathic pain (wherein classical single target opioids have low efficacy) with the latter having a predicted reduced tolerance profile. BU0807 is a buprenorphine derivative with mixed MOP/NOP agonist activity and this was shown to be effective in abdominal pain. SR16435 and GRT6005 (cebranopadol) are mixed MOP/MOP agonists with varying degrees of partial agonism. Both displayed significant antinociceptive activity and reduced tolerance potential in preclinical models. SUMMARY: There is growing evidence for and interest in the design and evaluation of mixed opioids that extend beyond the MOP/DOP pairing to now include NOP. Indeed, a mixed MOP/NOP ligand is close to the clinic; this will reinvigorate the search for other mixed molecules with reduced side-effect profiles.
Authors: Robert M Caudle; Stephanie L Caudle; Natalie D Flenor; Eric L Rohrs; John K Neubert Journal: Front Pharmacol Date: 2020-12-03 Impact factor: 5.810
Authors: Rakesh H Vekariya; Wei Lei; Abhisek Ray; Surendra K Saini; Sixue Zhang; Gabriella Molnar; Deborah Barlow; Kelly L Karlage; Edward J Bilsky; Karen L Houseknecht; Tally M Largent-Milnes; John M Streicher; Subramaniam Ananthan Journal: J Med Chem Date: 2020-06-30 Impact factor: 8.039