Opioid Peptidomimetics: Leads for the Design of Bioavailable Mixed Efficacy μ Opioid Receptor (MOR) Agonist/δ Opioid Receptor (DOR) Antagonist Ligands

Abstract

We have previously described opioid peptidomimetic, 1, employing a tetrahydroquinoline scaffold and modeled on a series of cyclic tetrapeptide opioid agonists. We have recently described modifications to these peptides that confer a mu opioid receptor (MOR) agonist, delta opioid receptor (DOR) antagonist profile, which has been shown to reduce the development of tolerance to the analgesic actions of MOR agonists. Several such bifunctional ligands have been reported, but none has been demonstrated to cross the blood brain barrier. Here we describe the transfer of structural features that evoked MOR agonist/DOR antagonist behavior in the cyclic peptides to the tetrahydroquinoline scaffold and show that the resulting peptidomimetics maintain the desired pharmacological profile. Further, the 4R diastereomer of 1 was fully efficacious and approximately equipotent to morphine in the mouse warm water tail withdrawal assay following intraperitoneal administration and thus a promising lead for the development of opioid analgesics with reduced tolerance.

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

“…Specifically, the 2-methylindanyl analogue was synthesized via an aldol condensation followed by a hydrogenation as previously described 1 to form aniline intermediate 7f . The 1-methylindanyl analogues were synthesized as a racemic mixture using a slight modification of methodology originally developed by Kolanos et al 30 that begins with a condensation reaction between indene and 4-acetamidobenzaldehyde, the product of which was hydrogenated and deprotected to yield an aniline intermediate 7g .…”

“…1–5 Co-administration of a MOR agonist with a δ-opioid receptor DOR antagonist 6–8 produces antinociception with reduced risk of tolerance and dependence, implicating the importance of reduced DOR signaling in mitigating these undesired properties. However, multi-drug regimens may produce pharmacokinetic complications and lead to low patient compliance.…”

“…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.…”

Synthesis of Carfentanil Amide Opioids Using the Ugi Multicomponent Reaction

“…9 Systemically active peptidomimetics and nonpeptide small molecules have also been reported with a similar pharmacological profile. 10 An example of a mixed agonist small molecule is SoRI 9409, which showed a preferable side effect profile to morphine. However, SoRI 9409 produced limited antinociception in thermal pain models, thereby limiting its potential therapeutic value.…”

Probes for narcotic receptor mediated phenomena 49. N-substituted rac-cis-4a-arylalkyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ols

“…In principle, then, substituent modifications at these positions could lead to compounds that interact with a desirable combination of $\tilde{\mu }$ and δ-opioid receptor affinity. It has been found that compounds that combine both μ-agonist and δ -antagonist behavior can minimize at least some of the undesired side-effects that are frequently observed with the use of opioid analgesics[5-7]. It has also been noted that a δ-agonist can counteract the respiratory depression induced by μ-agonists without interfering with antinociceptive activity [8].…”