Strategies to Improve Opioid Analgesia: Nociceptin Receptor Agonists and Intranasal Delivery in Monkeys.

There are two general approaches for improving pain control with opioids: identifying novel analgesics without μ-opioid receptor side effects, and developing strategies to optimize clinically used opioids. This thesis investigates a novel target for pain control (the nociceptin/orphanin FQ (NOPr) receptor), as well as the potential for improving current and future opioid medications by utilizing the intranasal (IN) route of delivery. In rhesus monkeys, NOPr agonists have been shown to produce analgesia in the absence of unwanted μ-receptor mediated effects. Other behaviors produced through NOP receptors have not been characterized. This thesis established for the first time in monkeys that the NOPr agonist Ro 64-6198 produced discriminative stimulus effects that were behaviorally and pharmacologically distinct from other opioid receptors, but were similar to the benzodiazepine, diazepam. In contrast to previous work, Ro 64-6198 did not produce antinociception in the monkey tail withdrawal assay, suggesting that this effect may be more variable than previously thought. IN drug administration offers several benefits for developing and administering therapeutics. Despite the favorable profile, IN delivery is employed less frequently than other parenteral routes, and functional animal models for IN delivery are not well established. This thesis reports the first model to measure the analgesic effects of intranasally administered opioids in rhesus monkeys. The effects of IN fentanyl and buprenorphine were found to be dose-dependent; a comparison to intramuscular (IM) administration suggested that IN delivery may result in a faster onset of action, and produce greater analgesia at lower doses. The translational aspects of this model were further explored by studying the actions of IN naloxone (NLX), a drug that is routinely used to reverse opioid toxicity, and where some questions remain about its potency and effectiveness relative to other routes. IN and IV NLX were found to be equipotent in reversing fentanyl-induced antinociception, however there was a trend for IV administration to produce larger decreases. Data obtained from PET images showed a similar trend for receptor occupancy. Overall, this thesis expanded the behavioral profile of NOPr agonists in monkeys, and provided a framework to investigate the IN delivery of novel and clinically used opioids.PhDPharmacologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/120776/1/sacconep_1.pd

Ortho-Fluorination of azophenols increases the mesophase stability of photoresponsive hydrogen-bonded liquid crystals

Photoresponsive liquid crystals (LCs) whose alignment can be controlled with UV-Visible light are appealing for a range of photonic applications. From the perspective of exploring the interplay between the light response and the self-assembly of the molecular components, supramolecular liquid crystals are of particular interest. They allow elaborating the structure-property relationships that govern the optical performance of LC materials by subtle variation of the chemical structures of the building blocks. Herein we present a supramolecular system comprising azophenols and stilbazoles as hydrogen-bond donors and acceptors, respectively, and show that ortho-fluorination of the azophenol dramatically increases the thermal stability of the LC phases, an important characteristics in their further utilization in photonics. The systems exhibit fast photoinduced order-disorder transitions, and rapid recovery of the liquid-crystalline state once the light irradiation is ceased, due to the photochemical properties of azophenols

Supramolecular modification of ABC triblock terpolymers in confinement assembly

The self-assembly of AB diblock copolymers in three-dimensional (3D) soft confinement of nanoemulsions has recently become an attractive bottom up route to prepare colloids with controlled inner morphologies. In that regard, ABC triblock terpolymers show a more complex morphological behavior and could thus give access to extensive libraries of multicompartment microparticles. However, knowledge about their self-assembly in confinement is very limited thus far. Here, we investigated the confinement assembly of polystyrene-block-poly(4-vinylpyridine)-block-poly(tert-butyl methacrylate) (PS-b-P4VP-b-PT or SVT) triblock terpolymers in nanoemulsion droplets. Depending on the block weight fractions, we found spherical microparticles with concentric lamella–sphere (ls) morphology, i.e., PS/PT lamella intercalated with P4VP spheres, or unusual conic microparticles with concentric lamella–cylinder (lc) morphology. We further described how these morphologies can be modified through supramolecular additives, such as hydrogen bond (HB) and halogen bond (XB) donors. We bound donors to the 4VP units and analyzed changes in the morphology depending on the binding strength and the length of the alkyl tail. The interaction with the weaker donors resulted in an increase in volume of the P4VP domains, which depends upon the molar fraction of the added donor. For donors with a high tendency of intermolecular packing, a visible change in the morphology was observed. This ultimately caused a shape change in the microparticle. Knowledge about how to control inner morphologies of multicompartment microparticles could lead to novel carbon supports for catalysis, nanoparticles with unprecedented topologies, and potentially, reversible shape changes by light actuation

Halogen bonding stabilizes a cis-azobenzene derivative in the solid state: A crystallographic study

Crystals of trans- and cis-isomers of a fluorinated azobenzene derivative have been prepared and characterized by single-crystal X-ray diffraction. The presence of F atoms on the aromatic core of the azobenzene increases the lifetime of the metastable cis-isomer, allowing single crystals of the cis-azobenzene to be grown. Structural analysis on the cis-azobenzene, complemented with density functional theory calculations, highlights the active role of the halogen-bond contact (N...I synthon) in promoting the stabilization of the cis-isomer. The presence of a long aliphatic chain on the azobenzene unit induces a phase segregation that stabilizes the molecular arrangement for both the trans- and cis-isomers. Due to the rarity of cis-azobenzene crystal structures in the literature, our paper makes a step towards understanding the role of non-covalent interactions in driving the packing of metastable azobenzene isomers. This is expected to be important in the future rational design of solid-state, photoresponsive materials based on halogen bonding. We show by single-crystal X-ray diffraction studies and computational analysis that halogen bonding can stabilize a metastable cis-azobenzene derivative in the solid state

Electron concentration effects on the Shastry-Sutherland phase stability in Ce_{2-x}Pd_{2+y}In_{1-z} solid solutions

The stability of a Shastry-Sutherland ShSu phase as a function of electron concentration is investigated through the field dependence of thermal and magnetic properties of the solid solution Ce_{2-x}Pd_{2+y}In_{1-z} in the antiferromagnetic branch. In these alloys the electronic (holes) variation is realized by increasing $Pd$ concentration. The AF transition T_M decreases from 3.5K to 2.8K as $Pd$ concentration increases from y=0.2 to y=0.4. By applying magnetic field, the ShSu phase is suppressed once the field induced ferromagnetic polarization takes over at a critical field B_{cr} which increases with $Pd$ content. A detailed analysis around the critical point reveals a structure in the maximum of the dM/dB derivative, which is related with incipient steps in the magnetization M(B) as predicted by the theory for the ShSu lattice. The crossing of M(B) isotherms, observed in ShSu prototype compounds, is also analyzed. The effect of $In$ substitution by $Pd$ is interpreted as an increase of the number of 'holes' in the conduction band and results in a unique parameter able to describe the variation of the magnetic properties along the studied range of concentration.Comment: 8 pages, 11 figure

Halogen bonding enhances nonlinear optical response in poled supramolecular polymers

We demonstrate that halogen bonding strongly enhances the nonlinear optical response of poled supramolecular polymer systems. We compare three nonlinear optical chromophores with similar electronic structures but different bond-donating units, and show that both the type and the strength of the noncovalent interaction between the chromophores and the polymer matrix play their own distinctive roles in the optical nonlinearity of the systems

Effect of Al doping on the optical phonon spectrum in Mg(1-x)Al(x)B(2)

Raman and infrared absorption spectra of Mg(1-x)Al(x)B(2) have been collected for 0<x<0.5 in the spectral range of optical phonons. The x-dependence of the peak frequency, the width and the intensity of the observed Raman lines has been carefully analized. A peculiar x-dependence of the optical modes is pointed out for two different Al doping ranges. In particular the onset of the high-doping structural phase previously observed in diffraction measurements is marked by the appearence of new spectral components at high frequencies. A connection between the whole of our results and the observed suppression of superconductivity in the high doping region is established

Hydrogen-bonded liquid crystals with broad-range blue phases

We report a modular supramolecular approach for the investigation of chirality induction in hydrogen-bonded liquid crystals. An exceptionally broad blue phase with a temperature range of 25 °C was found, which enabled its structural investigation by solid state 19F-NMR studies and allowed us to report order parameters of the blue phase I for the first time

Coordination networks incorporating halogen-bond donor sites and azobenzene groups

Two Zn coordination networks, [Zn(1)(Py)2]2(2-propanol)n (3) and [Zn(1)2(Bipy)2](DMF)2n (4), incorporating halogen-bond (XB) donor sites and azobenzene groups have been synthesized and fully characterized. Obtaining 3 and 4 confirms that it is possible to use a ligand wherein its coordination bond acceptor sites and XB donor sites are on the same molecular scaffold (i.e., an aromatic ring) without interfering with each other. We demonstrate that XBs play a fundamental role in the architectures and properties of the obtained coordination networks. In 3, XBs promote the formation of 2D supramolecular layers, which, by overlapping each other, allow the incorporation of 2-propanol as a guest molecule. In 4, XBs support the connection of the layers and are essential to firmly pin DMF solvent molecules through I⋯O contacts, thus increasing the stability of the solvated systems