Development and in Vitro Characterization of a Novel Bifunctional μ-Agonist/δ-Antagonist Opioid Tetrapeptide

Abstract

The development of tolerance to and dependence on opioid analgesics greatly reduces their long-term usefulness. Previous studies have demonstrated that co-administration of a mu opioid receptor (MOR) agonist and delta opioid receptor (DOR) antagonist can decrease MOR agonist induced tolerance and dependence development after chronic exposure. Clinically, a single ligand displaying multiple efficacies (e.g. MOR agonism concurrently with DOR antagonism) would be of increased value over two drugs administered simultaneously. Guided by modeling of receptor-ligand complexes we have developed a series of potent non-selective opioid tetrapeptides that have differing efficacy at MOR and DOR. In particular, our lead peptide (KSK-103) binds with equal affinity to MOR and DOR but acts as a MOR agonist with similar efficacy but greater potency than morphine and a DOR antagonist in cellular assays measuring both G protein stimulation and adenylyl cyclase inhibition.

Antinociceptive profile of LP1, a non-peptide multitarget opioid ligand

“…Indeed, an improved antinociception and a low propensity to tolerance development were reported for ligands possessing mixed MOR-DOR opioid activity. These pharmacological effects have been described for the DOR antagonist-MOR agonist peptidic ligands KSK-103 and UFP-505 (Purington et al, 2011;Balboni et al, 2010), as well as for the MOR-DOR peptidic agonists MMP2200 and BVD03 (Lowery et al, 2011;Vandormael et al, 2011). We previously identified a compound based on the 6,7-benzomorphan structure, 3-[(2R,6R,11R)-8-hydroxy-6, 11-dimethyl-1,4,5,6-tetrahydro-2,6-methano-3-benzazocin-3(2 H)-yl]-N-phenylpropanamide (LP1, Fig.…”

“…Opioids that combine MOR agonist-DOR antagonist activity (Purington et al, 2011;Balboni et al, 2010) or MOR agonist-DOR agonist activity (Lee et al, 2011;Vandormael et al, 2011) may be effective antinociceptive agents that are able to attenuate MOR-mediated side effects. In this regard, the data collected for LP1 are consistent with its low capability to induce tolerance (Pasquinucci et al, 2012).…”

Further Optimization and Evaluation of Bioavailable, Mixed-Efficacy μ-Opioid Receptor (MOR) Agonists/δ-Opioid Receptor (DOR) Antagonists: Balancing MOR and DOR Affinities

“…However, multi-drug regimens may produce pharmacokinetic complications and lead to low patient compliance. 9–11 Thus, we 1–2, 12–14 and others 3–5,15,16 have pursued the development of bifunctional, mixed-efficacy MOR agonist/DOR antagonist ligands. We first reported the synthesis of a high-affinity (nanomolar binding) opioid receptor peptidomimetic with selectivity for MOR in 1998.…”

Modulation of Opioid Receptor Ligand Affinity and Efficacy Using Active and Inactive State Receptor Models

“…Recently, however, it has been recognized that the simultaneous modulation of multiple targets may generate a more desirable drug profile, in some cases even reducing the development of negative side effects (1, 2). This concept is illustrated in the field of opioid analgesics, where the co-administration of a mu opioid receptor (MOR) agonist with a delta opioid receptor (DOR) antagonist provides all the expected analgesia of a MOR agonist, but with reduced negative side effects, such as constipation and respiratory depression and, more interestingly, reduced tolerance and dependence liabilities (3–7), features that limit the clinical use of opioid analgesics (8). …”