Johannes Schütz

Peripheral versus central antinociceptive actions of 6-amino acid-substituted derivatives of 14-O-methyloxymorphone in acute and inflammatory pain in the rat.

Opioid analgesics with restricted access to the central nervous system represent a new approach to the treatment of severe pain with an improved safety profile. The objective of this study was to investigate the peripheral and central components of the antinociceptive actions of the 6-amino acid conjugates (glycine, alanine, and phenylalanine) of 14-O-methyloxymorphone. Their antinociceptive activities were compared with those of the centrally penetrating μ-opioid agonists morphine, fentanyl, and 14-O-methyloxymorphone. In the tail-flick test in rats, the 6-amino acid conjugates were 45- to 1170-fold more potent than morphine after i.c.v. administration and 19- to 209-fold after s.c. administration. They showed potencies similar to fentanyl after s.c. administration and were more potent after i.c.v. application. The time course of action was different between s.c. and i.c.v. administration, with significant long-lasting effects after i.c.v. administration. Systemic administration of the peripherally selective opioid antagonist naloxone methiodide antagonized the effects after s.c. but not after i.c.v. administration in the tail-flick test. Subcutaneous 6-amino acid derivatives also elicited antihyperalgesic effects in the formalin test in rats, which were reversed by systemically administered naloxone methiodide. Although morphine exerts its analgesic effects by central and peripheral mechanisms, the investigated new opioids interact primarily with peripheral opioid receptors after s.c. administration. The present data indicate that the 6-amino acid conjugates of 14-O-methyloxymorphone have limited access to the central nervous system and can mediate antinociception at peripheral sites. Also, they might find clinical application when the central actions of opioids are unwanted.

Morphinans and isoquinolines: Acetylcholinesterase inhibition, pharmacophore modeling, and interaction with opioid receptors

Following indications from pharmacophore-based virtual screening of natural product databases, morphinan and isoquinoline compounds were tested in vitro for acetylcholinesterase (AChE) inhibition. After the first screen, active and inactive compounds were used to build a ligand-based pharmacophore model in order to prioritize compounds for biological testing. Among the virtual hits tested, the enrichment of actives was significantly higher than in a random selection of test compounds. The most active compounds were biochemically tested for their activity on mu, delta, and kappa opioid receptors.

14-Methoxymetopon, a very potent μ-opioid receptor-selective analgesic with an unusual pharmacological profile

14-Methoxymetopon is a potent opioid analgesic. When given systemically, it is approximately 500-fold more active than morphine. However, this enhanced potency is markedly increased with either spinal or supraspinal administration, where its analgesic activity is more than a million-fold greater than morphine. It was mu-opioid receptor selective in binding assays and its analgesia was blocked only by mu-opioid receptor-selective antagonists. Yet, it had a different selectivity profile than either morphine or morphine-6beta-glucuronide. Unlike morphine, 14-methoxymetopon was antagonized by 3-O-methylnaltrexone, it was sensitive to antisense probes targeting exons 1, 2 and 8 of the opioid receptor gene and was inactive both spinally and supraspinally in CXBK mice. Although it retarded gastrointestinal transit, it displayed a ceiling effect with no dose lowering transit by more than 65%, in contrast to the complete inhibition of transit by morphine. These finding demonstrate that 14-methoxymetopon is a highly potent mu-opioid with a pharmacological profile distinct from that of the traditional mu-opioid morphine.

N,N'-Di(alkyloxy)imidazolium Salts: New Patent-free Ionic Liquids and NHC Precatalysts

1-Hydroxyimidazole-3-oxides (2-H, 2-Me) were alkylated with (RO)2SO2 (R =Me, Et) to give the new 1,3-di(alkyloxy)imidazolium cations which were isolated as hexafluorophosphates. Ion metathesis yielded new hydrophobic ionic liquids (bis(trifluoromethanesulfonyl)imides, tris(pentafluoroethyl) trifluorophosphates). Bromination afforded 2-bromo derivatives which were converted to Ni and Pd N-heterocyclic carbene complexes by oxidative insertion. Fifteen crystal structures were determined by X-ray diffraction. The N-alkyloxy groups are twisted out of the imidazole ring plane and adopt either syn or anti conformations in the solid state.

Solvatochromism, halochromism, and preferential solvation of new dipolar guaiazulenyl 1,4-benzoquinone methidesElectronic supplementary information (ESI) available: Absorption maxima of the dyes 6–10 in seven binary solvent mixtures. See http://www.rsc.org/suppdata/ob/b2/b209555f/

The synthesis and the solvatochromic properties of five dyes, obtained by condensation of guaiazulene with 4-hydroxybenzaldehydes, are described. Crystal structures of a quinoid dye and a phenolic dye precursor are presented. The dyes are sensitive to the dipolarity-polarizability of the medium and to the hydrogen-bond donor ability of protic solvents. Their solvatochromism is discussed in terms of Kamlet-Tafts pi* and alpha scales, and their difference in behaviour is interpreted. Alkali and alkaline earth metal salts effect halochromism, with one exception due to extreme steric hindrance. Thus, this dye is capable of measuring solvent polarities without sensing the presence of electrolytes. Preferential solvation of the dyes in a series of binary solvent mixtures is explained quantitatively by solvent-exchange models.

Binding characteristics of [3H]14-methoxymetopon, a high affinity mu-opioid receptor agonist.

The highly potent µ‐opioid receptor agonist 14‐methoxymetopon (4,5α‐epoxy‐3‐hydroxy‐14β‐methoxy‐5β,17‐dimethylmorphinan‐6‐one) was prepared in tritium labelled form by a catalytic dehalogenation method resulting in a specific radioactivity of 15.9 Ci/mmol. Opioid binding characteristics of [3H]14‐methoxymetopon were determined using radioligand binding assay in rat brain membranes. [3H]14‐Methoxymetopon specifically labelled a single class of opioid sites with affinity in low subnanomolar range (Ki = 0.43 nm) and maximal number of binding sites of 314 fmol/mg protein. Binding of [3H]14‐methoxymetopon was inhibited by ligands selective for the µ‐opioid receptor with high potency, while selective κ‐opioids and δ‐opioids were weaker inhibitors. 14‐Methoxymetopon increased guanosine‐5′‐O‐(3‐[35S]thio)‐triphosphate ([35S]GTPγS) binding with an EC50 of 70.9 nm, thus, providing evidence for the agonist character of this ligand. The increase of [35S]GTPγS binding was inhibited by naloxone and selective µ‐opioid antagonists, indicating a µ‐opioid receptor‐mediated action. [3H]14‐Methoxymetopon is one of the few nonpeptide µ‐opioid receptor agonists available in radiolabelled form up to now. Due to its high affinity and selectivity, high stability and extremely low nonspecific binding (<10%), this radioligand would be an important and useful tool in probing µ‐opioid receptor mechanisms, as well as to promote a further understanding of the opioid system at the cellular and molecular level.

HS‐599: a novel long acting opioid analgesic does not induce place‐preference in rats

When administered subcutaneously HS‐599, a new didehydroderivative of buprenorphine (18,19‐dehydrobuprenorphine), produced a long‐lasting antinociceptive response in rats. Its potency exceeded twice that of buprenorphine. In the tail‐flick test it acted as a full agonist but in the plantar test only as a partial agonist. Whereas the μ‐opioid antagonists naloxone and naltrexone antagonized HS‐599 antinociception the δ‐opioid antagonist naltrindole and the κ‐opioid antagonist nor‐binaltorphimine did not. Unlike buprenorphine and morphine, HS‐599 never induced conditioned place‐preference in rats. In radioligand binding assays, compared with buprenorphine HS‐599 had 3 fold higher μ‐opioid receptor affinity but lower δ‐ and κ‐opioid receptor affinity. In isolated guinea‐pig ileum preparations, HS‐599 only partially inhibited the electrically‐stimulated contraction, acting as a partial opioid agonist. When tested against the μ‐opioid receptor agonist dermorphin, it behaved as a non‐equilibrium antagonist. Conversely, in mouse vas deferens (rich in δ‐opioid receptors) and rabbit vas deferens preparations (rich in κ‐opioid receptors) HS‐599 acted as a pure equilibrium antagonist, shifting the log‐concentration‐response curves of the δ‐opioid agonist deltorphin I and the κ‐opioid agonist U‐69593 to the right. In conclusion, HS‐599 is a novel buprenorphine derivative with higher affinity, selectivity and potency than the parent compound, for μ‐opioid receptors. It produces intense and long‐lasting antinociception and does not induce place‐preference in rats.

Novel Delta-Opioid-Receptor-Selective Ligands in the 14-Alkoxy-Substituted Indolo- and Benzofuromorphinan Series

Several new indolo- and benzofuromorphinans substituted at the positions 5 and 14 were prepared and tested in vitro by means of opioid-receptor binding and functional ([35S]GTPγS binding) assays. All compounds 1 – 11 displayed high affinity for δ opioid-binding sites (Table 1). Compound 4 proved to be an agonist, and all other compounds were antagonists. The presence of a Me group at position 5 induced no change in δ affinity (see 1vs.3), but decreased the μ and κ affinities. An EtO group at position 14 conferred a very high affinity and also high selectivity to δ opioid receptors (see 2 and 10). Chain elongation of the 14-alkoxy group resulted in compounds with reduced δ affinity and selectivity (see 4 and 11 and also 5 – 9). The results of the present study indicate that the 5- and 14-positions of indolo- and benzofuromorphinans represent critical sites that could be a trigger to develop new compounds with increased δ affinity and/or selectivity.

Synthesis and pharmacological activities of 6-glycine substituted 14-phenylpropoxymorphinans, a novel class of opioids with high opioid receptor affinities and antinociceptive potencies.

The synthesis and the effect of a combination of 6-glycine and 14-phenylpropoxy substitutions in N-methyl- and N-cycloproplymethylmorphinans on biological activities are described. Binding studies revealed that all new 14-phenylpropoxymorphinans (11−18) displayed high affinity to opioid receptors. Replacement of the 14-methoxy group with a phenylpropoxy group led to an enhancement in affinity to all three opioid receptor types, with most pronounced increases in δ and κ activities, hence resulting in a loss of μ receptor selectivity. All compounds (11−18) showed potent and long-lasting antinociceptive effects in the tail-flick test in rats after subcutaneous administration. For the N-methyl derivatives 13 and 14, analgesic potencies were in the range of their 14-methoxy analogues 9 and 10, respectively. Even derivatives 15−18 with an N-cyclopropylmethyl substituent acted as potent antinociceptive agents, being several fold more potent than morphine. Subcutaneous administration of compounds 13 and 14 produced significant and prolonged antinociceptive effects mediated through peripheral opioid mechanisms in carrageenan-induced inflammatory hyperalgesia in rats.

Functionalization of the Carbonyl Group in Position 6 of Morphinan-6-ones. Development of Novel 6-Amino and 6-Guanidino Substituted 14-Alkoxymorphinans

The well-known opioid agonists, oxycodone and oxymorphone, and the opioid antagonists, naloxone and naltrexone, are commonly used clinical agents and research tools in the opioid field. They belong to the class of morphinan-6-ones, and produce their pharmacological effects by interacting with opioid receptors, i.e. mu (MOR), delta (DOR) and kappa (KOR). The search for potent agonists and antagonists has continuously engaged the interest of pharmaceutical research, aiming for the identification of safer therapeutic agents or discovery of opioids with novel therapeutic properties and with lesser unwanted side effects. The chemically highly versatile carbonyl group in position 6 of mophinan-6-ones permits functionalization and modification leading to numerous opioid ligands. We have focused on representative examples of various derivatives and interesting approaches for the development of structurally distinct molecules with substitution at C6 (e.g. 6-methylene, 6-hydroxy, 6-amido, bifunctional ligands), as preclinically and clinically valuable opioids. In this work, the development of 6-amino and 6-guanidino substituted 14-alkoxymorphinans, including the synthesis and pharmacological investigations is presented. The new approach represented by the introduction of amino and guanidino groups into position 6 of the morphinan skeleton of 14-O-methyloxymorphone, led to compounds with high efficacy, MOR affinity and selectivity, which act as potent antinociceptive agents. Altogether, as a consequence of target drug design and synthetic efforts in the field of morphinan-6-ones, we achieve a better understanding of the function of the opioid system, and such efforts may open new avenues for further investigations.