Orvinols with mixed kappa/mu opioid receptor agonist activity.

Dual-acting kappa opioid receptor (KOR) agonist and mu opioid receptor (MOR) partial agonist ligands have been put forward as potential treatment agents for cocaine and other psychostimulant abuse. Members of the orvinol series of ligands are known for their high binding affinity to both KOR and MOR, but efficacy at the individual receptors has not been thoroughly evaluated. In this study, it is shown that a predictive model for efficacy at KOR can be derived, with efficacy being controlled by the length of the group attached to C20 and by the introduction of branching into the side chain.

Fumaroylamino-4,5-epoxymorphinans and related opioids with irreversible μ opioid receptor antagonist effects.

We have previously shown that cinnamoyl derivatives of 14β-amino-17-cyclopropylmethyl-7,8-dihydronormorphinone and 7α-aminomethyl-6,14-endoethanonororipavine have pronounced pseudoirreversible μ opioid receptor (MOR) antagonism. The present communication describes the synthesis and evaluation of fumaroylamino analogues of these cinnamoylamino derivatives together with some related fumaroyl derivatives. The predominant activity of the new ligands was MOR antagonism.

Reversible, allosteric small-molecule inhibitors of regulator of G protein signaling proteins.

Regulators of G protein signaling (RGS) proteins are potent negative modulators of G protein signaling and have been proposed as potential targets for small-molecule inhibitor development. We report a high-throughput time-resolved fluorescence resonance energy transfer screen to identify inhibitors of RGS4 and describe the first reversible small-molecule inhibitors of an RGS protein. Two closely related compounds, typified by CCG-63802 [((2E)-2-(1,3-benzothiazol-2-yl)-3-[9-methyl-2-(3-methylphenoxy)-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl]prop-2-enenitrile)], inhibit the interaction between RGS4 and Galpha(o) with an IC(50) value in the low micromolar range.

Proerectile effects of dopamine D2-like agonists are mediated by the D3 receptor in rats and mice.

Dopamine D(2)-like agonists induce penile erection (PE) and yawning in a variety of species, effects that have been suggested recently to be specifically mediated by the D(4) and D(3) receptors, respectively. The current studies were aimed at characterizing a series of D(2), D(3), and D(4) agonists with respect to their capacity to induce PE and yawning in the rat and the proerectile effects of apomorphine [(R)-(-)-5,6,6a,7-tetrahydro-6-methyl-4H-dibenzo-[de,g]quinoline-10,11-diol hydrochloride] in wild-type and D(4) receptor (R) knockout (KO) mice. All D(3) agonists induced dose-dependent increases in PE and yawning over a similar range of doses, whereas significant increases in PE or yawning were not observed with any of the D(4) agonists.

The discriminative stimulus effects of dopamine D2- and D3-preferring agonists in rats.

Rationale: Previous research has found the stimulus effects of dopamine D2- and D3-preferring agonists difficult to distinguish in drug discrimination studies. Antagonism studies suggest that the stimulus effects of both types of agonists may be mediated primarily through D2 receptors.

Objectives: The current study was designed to further assess the receptors mediating the stimulus effects of these agonists and to attempt to train rats to discriminate directly between D2- and D3-preferring dopamine agonists.

Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity.

S3I-201 (NSC 74859) is a chemical probe inhibitor of Stat3 activity, which was identified from the National Cancer Institute chemical libraries by using structure-based virtual screening with a computer model of the Stat3 SH2 domain bound to its Stat3 phosphotyrosine peptide derived from the x-ray crystal structure of the Stat3beta homodimer. S3I-201 inhibits Stat3.Stat3 complex formation and Stat3 DNA-binding and transcriptional activities.

Abrogation of heat shock protein 70 induction as a strategy to increase antileukemia activity of heat shock protein 90 inhibitor 17-allylamino-demethoxy geldanamycin.

17-Allylamino-demethoxy geldanamycin (17-AAG) inhibits the chaperone association of heat shock protein 90 (hsp90) with the heat shock factor-1 (HSF-1), which induces the mRNA and protein levels of hsp70. Increased hsp70 levels inhibit death receptor and mitochondria-initiated signaling for apoptosis. Here, we show that ectopic overexpression of hsp70 in human acute myelogenous leukemia HL-60 cells (HL-60/hsp70) and high endogenous hsp70 levels in Bcr-Abl-expressing cultured CML-BC K562 cells confers resistance to 17-AAG-induced apoptosis.

Synthetic applications of electrophilic fluorodesilylation.

Recently, with the appearance of electrophilic sources of fluorine including the commercially available N-F reagents, the concept of electrophilic fluorodesilylation has emerged as a new strategy to prepare a variety of fluorine containing compounds. This paper highlights how this concept has been applied to the preparation of a series of fluorinated molecules including fluoroaromatic compounds, fluoroalkenes, difluoroamides, difluoroalcohols, difluoroethers and alpha-fluorinated carbonyl derivatives.