LP1 and LP2: Dual-Target MOPr/DOPr Ligands as Drug Candidates for Persistent Pain Relief

Abstract

Although persistent pain is estimated to affect about 20% of the adult population, current treatments have poor results. Polypharmacology, which is the administration of more than one drug targeting on two or more different sites of action, represents a prominent therapeutic approach for the clinical management of persistent pain. Thus, in the drug discovery process the “one-molecule-multiple targets” strategy nowadays is highly recognized. Indeed, multitarget ligands displaying a better antinociceptive activity with fewer side effects, combined with favorable pharmacokinetic and pharmacodynamic characteristics, have already been shown. Multitarget ligands possessing non-opioid/opioid and opioid/opioid mechanisms of action are considered as potential drug candidates for the management of various pain conditions. In particular, dual-target MOPr (mu opioid peptide receptor)/DOPr (delta opioid peptide receptor) ligands exhibit an improved antinociceptive profile associated with a reduced tolerance-inducing capability. The benzomorphan-based compounds LP1 and LP2 belong to this class of dual-target MOPr/DOPr ligands. In the present manuscript, the structure–activity relationships and the pharmacological fingerprint of LP1 and LP2 compounds as suitable drug candidates for persistent pain relief is described.

Mu and Delta Opioid Receptor Targeting Reduces Connexin 43-Based Heterocellular Coupling during Neuropathic Pain

“…Our evidence suggests that CCI induces a robust intercellular coupling mediated by Cx43 and this phenomenon supports neuropathic pain chronicization. Simultaneous targeting of MOR and DOR was able to reverse this effect, maybe linked to an overall reduction of Cx43, consistent with previous published evidence [ 16 , 18 , 24 ].…”

“…LP2 treatment, in agreement with previous published research [ 16 , 18 , 24 ], was able to recover the withdrawal threshold of CCI rats at 9, 13, and 16 dpl, confirming the potential of dual-targeting agents to be used in chronic neuropathic pain. Such an antiallodynic effect was abolished by co-administration of the selective MOR antagonist NLX and the selective DOR antagonist NTD.…”

“…Although many drugs targeting opioid receptors are available to treat neuropathic pain, unfortunately they are often associated with severe side effects, and will not achieve sufficient pain relief at therapeutic doses [ 1 ]. In particular, drugs targeting the mu opioid receptor (MOR), such as morphine, are currently used to treat moderate to severe pain conditions, but their use in chronic pain is limited due to their poor tolerability profile [ 18 ]. Thus, there is an urgent need to develop new pharmacological agents, able to maintain long-term analgesic efficacy with limited side-effects.…”

Multitargeted Opioid Ligand Discovery as a Strategy to Retain Analgesia and Reduce Opioid-Related Adverse Effects

“…13 As LP1 (43) antinociception (tf) was attenuated by icv but not sc naloxone methiodide (46) (Figure 13) (peripherally restricted opioid antagonist), it was clear that LP1 (43) crossed the BBB. 13 For rats given twice-daily doses of either LP1 (43) (4 mg/kg sc) or morphine (4) (Figure 1) (10 mg/kg sc) for 9 days, antinociceptive tolerance (tf) was fully developed by day 5 in the morphine-treated group, but in LP1-treated rats the tolerance only became evident on days 7 and 9 of the dosing regimen (Table 2). 43 This promising antinociception profile was extended to include the assessment of pain relief evoked in rat models of peripheral neuropathic pain and chronic inflammatory pain (Table 2).…”

“…13 This body of work led to the discovery of the MOP agonist/DOP antagonist ligand LP1 (43) (Figure 12), which has a N-phenylpropanamide substituent on the basic nitrogen. 13 In rats dosed chronically with either morphine or LP-1 (43), full antinociceptive (tf) tolerance was developed by days 7−9 in the LP1 group compared with day 5 in the morphine group. 13 At the highest dose tested, LP1(43) inhibited gastrointestinal transit of a charcoal meal, albeit with a lower potency relative to morphine (Table 2).…”