Novel Dual-Target μ-Opioid Receptor and Dopamine D₃ Receptor Ligands as Potential Nonaddictive Pharmacotherapeutics for Pain Management

Abstract

The need for safer pain-management therapies with decreased abuse liability inspired a novel drug design that retains μ-opioid receptor (MOR)-mediated analgesia, while minimizing addictive liability. We recently demonstrated that targeting the dopamine D3 receptor (D3R) with highly selective antagonists/partial agonists can reduce opioid self-administration and reinstatement to drug seeking in rodent models without diminishing antinociceptive effects. The identification of the D3R as a target for the treatment of opioid use disorders prompted the idea of generating a class of ligands presenting bitopic or bivalent structures, allowing the dual-target binding of the MOR and D3R. Structure–activity relationship studies using computationally aided drug design and in vitro binding assays led to the identification of potent dual-target leads (23, 28, and 40), based on different structural templates and scaffolds, with moderate (sub-micromolar) to high (low nanomolar/sub-nanomolar) binding affinities. Bioluminescence resonance energy transfer-based functional studies revealed MOR agonist–D3R antagonist/partial agonist efficacies that suggest potential for maintaining analgesia with reduced opioid-abuse liability.

Structure Activity Relationships for a Series of Eticlopride-Based Dopamine D2/D3 Receptor Bitopic Ligands

“…This is in contrast to previously reported and highly D 3 R selective antagonists and partial agonists. , Importantly, this study provides the necessary SAR to position long linker chains and/or sterically bulky groups on the eticlopride molecule to create bioconjugate D 2 R/D 3 R tools of interest such as fluorescent ligands and Drugs Acutely Restricted by Tethering (DARTs) . Further, the design of novel dual target mu opioid receptor and D 3 R partial agonists as potentially nonaddictive analgesics has already been inspired by these novel eticlopride ligands …”

Biased Opioid Ligands: Revolution or Evolution?

“…Allosteric ligands at the MOR could be also interesting as they could be used to enhance the effects of either the exogenous orthosteric agonists when administrated together or the endogenous opioid peptides released in stress or pain condition ( 49 ). Another strategy could be the development of dual-target ligands directed to both MOR and another receptor, including for instance dopamine D3 receptor ( 50 ). Whether biased ligands, ligands with low selectivity toward different opioid receptors, or bivalent ligands, the development of an analgesic compound free of side effects and with low abuse potential seems to be a way still paved with some difficulties.…”

Fentanyl Structure as a Scaffold for Opioid/Non-Opioid Multitarget Analgesics

“…Qian et al demonstrated feasibility of targeting MOR/D 2 -likeRs heterodimers by long molecules containing alkaloid MOR-related fragments (naltrexone, hydromorphone) [ 68 ]. Bonifazi et al synthesized MOR-D 3 R bitopic/bivalent compounds in which opioid fragment was based on acyclic opioids [ 75 ].…”

“…As a side note, let us mention that an avenue that might deserve exploration is using fentanyl scaffold for designing compact (‘merged’) MOR/D 4 R multifunctional drugs. Fentanyl ( 1.1 ) has been recently shown to have almost no D 2 R (K i = 21,000 nM) and no D 3 R binding (K i = 26,200 nM), but some moderate, submicromolar affinity for D 4 R (K i = 554 nM) [ 75 ].…”