Synthesis and Investigation of Mixed µ-Opioid and δ-Opioid Agonists as Possible Bivalent Ligands for Treatment of Pain.

Several studies have suggested functional association between µ-opioid and δ-opioid receptors and showed that µ-activity could be modulated by δ-ligands. The general conclusion is that agonists for the δ-receptor can enhance the analgesic potency and efficacy of µ-agonists. Our preliminary investigations demonstrate that new bivalent ligands constructed from the µ-agonist fentanyl and the δ-agonist enkephalin-like peptides are promising entities for creation of new analgesics with reduced side effects for treatment of neuropathic pain. A new superposition of the mentioned pharmacophores led to novel µ-bivalent/δ-bivalent compounds that demonstrate both µ-opioid and δ-opioid receptor agonist activity and high efficacy in anti-inflammatory and neuropathic pain models with the potential of reduced unwanted side effects.

Fentanyl-related compounds and derivatives: current status and future prospects for pharmaceutical applications.

Fentanyl and its analogs have been mainstays for the treatment of severe to moderate pain for many years. In this review, we outline the structural and corresponding synthetic strategies that have been used to understand the structure-biological activity relationship in fentanyl-related compounds and derivatives and their biological activity profiles. We discuss how changes in the scaffold structure can change biological and pharmacological activities. Finally, recent efforts to design and synthesize novel multivalent ligands that act as mu and delta opioid receptors and NK-1 receptors are discussed.

Novel fentanyl-based dual µ/δ-opioid agonists for the treatment of acute and chronic pain.

UNLABELLED: Approximately one third of the adult U.S. population suffers from some type of on-going, chronic pain annually, and many more will have some type of acute pain associated with trauma or surgery. First-line therapies for moderate to severe pain include prescriptions for common mu opioid receptor agonists such as morphine and its various derivatives. The epidemic use, misuse and diversion of prescription opioids have highlighted just one of the adverse effects of mu opioid analgesics. Alternative approaches include novel opioids that target delta or kappa opioid receptors, or compounds that interact with two or more of the opioid receptors. AIMS: Here we report the pharmacology of a newly synthesized bifunctional opioid agonist (RV-Jim-C3) derived from combined structures of fentanyl and enkephalin in rodents. RV-Jim-C3 has high affinity binding to both mu and delta opioid receptors. MAIN METHODS: Mice and rats were used to test RV-Jim-C3 in a tailflick test with and without opioid selective antagonist for antinociception. RV-Jim-C3 was tested for anti-inflammatory and antihypersensitivity effects in a model of formalin-induced flinching and spinal nerve ligation. To rule out motor impairment, rotarod was tested in rats. KEY FINDINGS: RV-Jim-C3 demonstrates potent-efficacious activity in several in vivo pain models including inflammatory pain, antihyperalgesia and antiallodynic with no significant motor impairment. SIGNIFICANCE: This is the first report of a fentanyl-based structure with delta and mu opioid receptor activity that exhibits outstanding antinociceptive efficacy in neuropathic pain, reducing the propensity of unwanted side effects driven by current therapies that are unifunctional mu opioid agonists.

Effect of anchoring 4-anilidopiperidines to opioid peptides.

We report here the design, synthesis, and in vitro characterization of new opioid peptides featuring a 4-anilidopiperidine moiety. Despite the fact that the chemical structures of fentanyl surrogates have been found suboptimal per se for the opioid activity, the corresponding conjugates with opioid peptides displayed potent opioid activity. These studies shed an instructive light on the strategies and potential therapeutic values of anchoring the 4-anilidopiperidine scaffold to different classes of opioid peptides.

Recyclization reactions of 1-alkylpyrimidinium salts.

The reaction of 4-amino-2-benzyl-1-methyl-5-ethoxycarbonylpyrimidinium iodide (3) with alcoholic methylamine resulted in the formation of the methylimine of 2-amino-4-hydroxy-6-methylamino-5-phenylpyridine-3-carbaldehyde (5). Heating of the same pyrimidinium salt in benzylamine gave a mixture of products of two C-C recyclizations: 2-benzyl-4-benzylamino-5-carbamoylpyrimidine (7) and the benzylimine of 4-amino-2-benzyl-6-benzylaminopyrimidine-5-carbaldehyde (8). The reaction of 2-amino-1,4-dimethyl-5-ethoxycarbonylpyrimidinium iodide (10) with KOH ethanolic solution gave a single product of C-C-recyclization: 2-amino-5-acetyl-4-hydroxypyrimidine (11).

Synthesis and evaluation of 3-aminopropionyl substituted fentanyl analogues for opioid activity.

An enkephalin analogue coupled to 'aminofentanyl' has been synthesized and tested for biological activities at the mu and delta opioid receptors. Aminofentanyl which represents a structural derivative of fentanyl has been synthesized by acylation of 1-(2-phenethyl)-4-(N-anilino)piperidine with phthaloyl protected beta-alaninyl chloride in the presence of DIPEA, followed by deprotection with hydrazine hydrate. Aminofentanyl has also been successfully acylated with ethyl isocyanate, various acid anhydrides, to further investigate structure-activity relationships of these new fentanyl derivatives. Among the new derivatives compound 7 which carries a Tyr-D-Ala-Gly-Phe opioid message sequence showed good opioid affinity (1 nM at both delta and mu opioid receptors) and bioactivity (34.9 nM in MVD and 42 nM in GPI/LMMP bioassays).

4-{N-[2-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)-3-phenylpropionyl]anilino}-1-phenethylpiperidinium chloride methanol disolvate.

The structure of the title compound, a fentanyl derivative with formula C(36)H(36)N(3)O(3) (+)·Cl(-)·2CH(3)OH, crystallizes as a racemic mixture. The organic cation has an extended conformation and the structure displays O-H⋯O, O-H⋯Cl and N-H⋯Cl hydrogen bonding.