Ruben Vardanyan

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.

Development of potent μ and δ opioid agonists with high lipophilicity.

An SAR study on the Dmt-substituted enkephalin-like tetrapeptide with a N-phenyl-N-piperidin-4-ylpropionamide moiety at the C-terminal was performed and has resulted in highly potent ligands at μ and δ opioid receptors. In general, ligands with the substitution of D-Nle(2) and halogenation of the aromatic ring of Phe(4) showed highly increased opioid activities. Ligand 6 with good biological activities in vitro demonstrated potent in vivo antihyperalgesic and antiallodynic effects in the tail-flick assay.

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.

Synthesis and investigations of double-pharmacophore ligands for treatment of chronic and neuropathic pain.

Acids 9a-f as possible bivalent ligands designed as a structural combination of opioid mu-agonist (Fentanyl) and NSAID (Indomethacin) activities and produced compounds which were tested as analgesics. The obtained series of compounds exhibits low affinity and activity both at opioid receptors and as cyclooxygenase (COX) inhibitors. One explanation of the weak opioid activity could be stereochemical peculiarities of these bivalent compounds which differ significantly from the fentanyl skeleton. The absence of significant COX inhibitory properties could be explained by the required substitution of an acyl fragment in the indomethacin structure for 4-piperidyl.

Opioid and melanocortin receptors: do they have overlapping pharmacophores?

We have identified compound 1 as a novel ligand for opioid and melanocortin (MC) receptors, which is derived from the overlapping of a well known structure for the δ opioid receptor, 2,6‐dimethyltyrosine (Dmt)‐1,2,3,4‐tetrahydroisoquinoline‐3‐carboxylic acid (Tic), and a small molecule for the MC receptor, Tic‐DPhe(p‐Cl)‐piperidin‐4‐yl‐N‐phenyl‐propionamide. Ligand 1 showed that there is an overlapping pharmacophore between opioid and MC receptors through the Tic residue. The ligand displayed high biological activities at the δ opioid receptor (Ki = 0.38 nM in binding assay, EC50 = 0.48 nM in GTP‐γ‐S binding assay, IC50 = 74 nM in MVD) as an agonist instead of an antagonist and showed selective binding affinity (IC50 = 2.3 μM) at the MC‐3 receptor rather than at the MC‐5 receptor. A study of the structure‐activity relationships demonstrated that the residues in positions 2, 3, and the C‐terminus act as a pharmacophore for the MC receptors, and the residues in positions 1 and 2 act as a pharmacophore for the opioid receptors. Thus, this structural construct can be used to prepare chimeric structures with adjacent or overlapping pharmacophores for opioid and MC receptors.

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.

Classes of Piperidine-Based Drugs

This chapter describes piperidine-based drugs in accordance with their pharmacological classes and in order of their prevalence, which looks like this:

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.

Chapter 29 – Immunopharmacological Drugs

The immune system is a complex network of integrated combination of organs, tissues, cells, hormones, other chemical signaling molecules, and cell products such as antibodies that protect organism from potential pathogens (bacteria, viruses, parasites, fungi, and others) neutralizing them and eliminating disease. There are two general classes of immunotherapeutic drugs: those that stimulate and activate the immune system are called immunostimulants, and those that suppress the immune system are called immunosuppressants. Immunosuppressants are used to suppress the immune system in organ transplantations as antirejection drugs to prevent rejection of transplanted organs, and to treat autoimmune diseases such as rheumatoid arthritis, lupus, psoriasis, Crohn disease (a chronic inflammation of the digestive tract), multiple sclerosis, and alopecia, and to treat nonautoimmune diseases such as allergy. Immunosuppressants are a structurally and functionally heterogeneous group of drugs, and can be subclassified as xenobiotic and biological immunosuppressants. Xenobiotics, in turn, can be subcategorized as corticosteroids, antimetabolites, calcineurin inhibitors, protein kinase inhibitors of the mammalian target of rapamycin (mTOR inhibitors); mTOR is a protein kinase that regulates cell growth, cell proliferation, etc. Immunostimulants or immunopotentiators are chemical substances capable of increasing the overall activity of immune system represent an emerging class of drugs, which has shown some promise in the treatment of primary immunodeficiencies, cancers, and viral infection such as human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS). There are two main categories of immunostimulants: • Specific immunostimulants are those that stimulate an immune response to specific antigenic types. • Nonspecific immunostimulants are those that do not have antigenic specificity and are widely used in chronic infections, immunodeficiency, autoimmunity, and neoplastic diseases. Immunostimulants are classified as bacteria-derived immunostimulants, immunostimulants of mammalian origin, immunostimulants of endogenous origin, and small molecule immunostimulants. The immunosuppressants mycophenolate, cyclosporine, and tacrolimus are included in the list of Top 200 Drugs by sales for the 2010s. No immunostimulant is included in this list.

Drugs for Treating Respiratory System Diseases

Respiratory disease is considered any disorder that affects nasal cavities, the throat, the trachea, the bronchi and bronchioles, or lungs, generating shortness of breath (dyspnea), cough, or production of sputum. Any pathological problem in the lungs that prevents them from working properly is considered lung disease, including airway diseases, lung circulation diseases, and lung tissue diseases.