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1.
J Heterocycl Chem ; 54(2): 1228-1235, 2017 03.
Article in English | MEDLINE | ID: mdl-28819330

ABSTRACT

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.

2.
Future Med Chem ; 6(4): 385-412, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24635521

ABSTRACT

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.


Subject(s)
Analgesics, Opioid/chemistry , Fentanyl/chemistry , Analgesics, Opioid/chemical synthesis , Analgesics, Opioid/therapeutic use , Animals , Fentanyl/chemical synthesis , Fentanyl/therapeutic use , Humans , Neuralgia/drug therapy , Receptors, Opioid, delta/agonists , Receptors, Opioid, delta/metabolism , Receptors, Opioid, mu/agonists , Receptors, Opioid, mu/metabolism , Structure-Activity Relationship
3.
Life Sci ; 93(25-26): 1010-6, 2013 Dec 18.
Article in English | MEDLINE | ID: mdl-24084045

ABSTRACT

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.


Subject(s)
Acute Pain/drug therapy , Analgesics, Opioid/pharmacology , Chronic Pain/drug therapy , Enkephalins/pharmacology , Fentanyl/analogs & derivatives , Fentanyl/chemistry , Receptors, Opioid, delta/agonists , Receptors, Opioid, mu/agonists , Analgesics, Opioid/chemistry , Analgesics, Opioid/metabolism , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical/methods , Enkephalins/chemistry , Fentanyl/pharmacology , Male , Mice , Mice, Inbred ICR , Naloxone/pharmacology , Naltrexone/analogs & derivatives , Naltrexone/pharmacology , Narcotic Antagonists/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Opioid, delta/metabolism , Receptors, Opioid, mu/metabolism
4.
Bioorg Med Chem Lett ; 23(11): 3434-7, 2013 Jun 01.
Article in English | MEDLINE | ID: mdl-23623418

ABSTRACT

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.


Subject(s)
Opioid Peptides/chemistry , Piperidines/chemistry , Animals , Cell Line , Fentanyl/chemistry , Humans , Kinetics , Mice , Opioid Peptides/chemical synthesis , Opioid Peptides/metabolism , Piperidines/chemical synthesis , Piperidines/metabolism , Protein Binding , Receptors, Opioid, delta/chemistry , Receptors, Opioid, delta/genetics , Receptors, Opioid, delta/metabolism , Receptors, Opioid, mu/chemistry , Receptors, Opioid, mu/genetics , Receptors, Opioid, mu/metabolism , Structure-Activity Relationship
5.
Heterocycl Comm ; 17(3-4): 129-133, 2011 Sep.
Article in English | MEDLINE | ID: mdl-25400328

ABSTRACT

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).

6.
Bioorg Med Chem Lett ; 16(18): 4946-50, 2006 Sep 15.
Article in English | MEDLINE | ID: mdl-16828552

ABSTRACT

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).


Subject(s)
Fentanyl/analogs & derivatives , Fentanyl/pharmacology , Narcotics/chemical synthesis , Narcotics/pharmacology , Animals , Fentanyl/chemical synthesis , Fentanyl/chemistry , Humans , Inhibitory Concentration 50 , Molecular Structure , Narcotics/chemistry , Picolines , Rats , Receptors, Opioid, delta/metabolism , Receptors, Opioid, mu/metabolism , Structure-Activity Relationship
7.
Acta Crystallogr Sect E Struct Rep Online ; 62(7): o2815-o2816, 2006 Jul.
Article in English | MEDLINE | ID: mdl-17268579

ABSTRACT

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.

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