Neurochemical regulators of food behavior for pharmacological treatment of obesity: current status and future prospects.

In recent decades, obesity has become a pandemic disease and appears to be an ultimate medical and social problem. Existing antiobesity drugs show low efficiency and a wide variety of side effects. In this review, we discuss possible mechanisms underlying brain-gut-adipose tissue axis, as well as molecular biochemical characteristics of various neurochemical regulators of body weight and appetite. Multiple brain regions are responsible for eating behavior, hedonic eating and food addiction. The existing pharmacological targets for treatment of obesity were reviewed as well.

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.

Chiral Effect of a Phe Residue in Position 3 of the Dmt1-L(or D)-Tic2 Analogues on Opioid Functional Activities.

In this letter, we describe a structure-activity relationships study, specifically related to the chirality of third amino acid residue in our H-Dmt-L(or D)-Tic analogues, of which C-terminus is attached to a piperidinyl moiety. Observed selectivities and functional activities of these analogues demonstrated that the chiralities of the second and third position residues are crucial for determining whether these ligands act as antagonists or agonists at the δ opioid receptor, but not at the µ opioid receptor.

Synthesis and biological evaluation of new opioid agonist and neurokinin-1 antagonist bivalent ligands.

Newly designed bivalent ligands-opioid agonist/NK1-antagonists have been synthesized. The synthesis of new starting materials-carboxy-derivatives of Fentanyl (1a-1c) was developed. These products have been transformed to 'isoimidium perchlorates' (2a-c). The new isoimidium perchlorates have been successfully implemented in nucleophilic addition reactions, with l-tryptophan 3,5-bis(trifluoromethyl)benzyl ester to give the target compounds-amides (3a-c). Perchlorates (2a-c) successfully undergo reactions with other nucleophiles such as alcohols, amines or hydrazines. The obtained compound 3b exhibited µ-opioid agonist activity and NK1-antagonist activity and may serve as a useful lead compound for the further design of a new series of opioid agonist/NK1-antagonist compounds.

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).

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.

Proton sharing and transfer in some zwitterionic compounds based on 4-oxo-4-((1-phenethylpiperidin-4-yl)(phenyl)amino)alcanoic acids.

Three compounds, each derived from Fentanyl and differing essentially only in the length of a carboxylic acid chain, were synthesized and yielded four crystal structures three of which share several structural similarities, including the length of the chain, while the fourth, with a shorter chain, is quite different. The chain length has a significant influence on the crystal structures formed. The 'three atom' chain compounds are all solvated zwitterions which feature a hydrogen-bonded 'dimer' between adjacent zwitterions. The formation of this large dimer leaves available a second carboxylate O atom to take part in hydrogen bonding interactions with solvent molecules. The shorter 'two atom' chain compound was difficult to crystallize and required the use of synchrotron radiation to measure X-ray diffraction data. It does not form the same dimer motif observed in the 'three atom' chain compounds and has not formally formed a zwitterion; although there is evidence of proton sharing or disorder X-ray data are insufficient to create a disordered model, and the compound was modeled as formally neutral based on O-H and N-H distances. Room temperature analyses showed the proton transfer behavior to be independent of crystal temperature, and nuclear magnetic resonance studies show proton transfer behavior in solution. The formation of a zwitterionic hydrogen-bonded dimer is implicated in providing some stability during crystal growth of the easily crystallized 'three atom' chain compounds.

Synthesis and Crystallographic Study of N'-(1-benzylpiperidin-4-yl)acetohydrazide.

As part of a study into new Fentanyl-derived opioid compounds with potent analgesic activity and reduced side effects the starting material title compound, C14H21N3O (1), was synthesized and characterized by NMR spectroscopy and single-crystal X-ray diffraction. The crystal structure is monoclinic Cc with unit cell parameters a = 14.1480(3) Å, b = 14.1720(4) Å, c = 27.6701(7) Å, ß = 96.956(1)°, α = γ = 90°. The compound has crystallized with four crystallographically unique molecules in the asymmetric unit; each molecule has a very similar conformation and an analysis of the structure shows that although all four unique molecules overlay very well there is no evidence of pseudo-symmetry which would relate the molecules in the higher symmetry space group C2/c. The crystal packing consists of two separate hydrogen bonded chains which are linked together to form a thick 2D structure in the ab plane.

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 delta 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 delta opioid receptor (Ki = 0.38 nM in binding assay, EC(50) = 0.48 nM in GTP-gamma-S binding assay, IC(50) = 74 nM in MVD) as an agonist instead of an antagonist and showed selective binding affinity (IC(50) = 2.3 muM) 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.

Development of novel enkephalin analogues that have enhanced opioid activities at both mu and delta opioid receptors.

Enkephalin analogues with a 4-anilidopiperidine scaffold have been designed and synthesized to achieve therapeutic benefit for the treatment of pain due to mixed mu and delta opioid agonist activities. Ligand 16, in which a Dmt-substituted enkephalin-like structure was linked to the N-phenyl-N-piperidin-4-yl propionamide moiety, showed very high binding affinities (0.4 nM) at mu and delta receptors with an increased hydrophobicity (aLogP = 2.96). This novel lead compound was found to have very potent agonist activities in MVD (1.8 nM) and GPI (8.5 nM) assays.

Understanding the structural requirements of 4-anilidopiperidine analogues for biological activities at mu and delta opioid receptors.

New 4-anilidopiperidine analogues in which the phenethyl group of fentanyl was replaced by several aromatic ring-contained amino acids (or acids) were synthesized to study the biological effect of the substituents on mu and delta opioid receptor interactions. These analogues showed broad (47 nM-76 microM) but selective (up to 17-fold) binding affinities at the mu opioid receptor over the delta opioid receptor, as predicted from the message-address concept.

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.