Simultaneous targeting of multiple opioid receptor types.

Abstract

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. 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. 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.