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Wennan Xiong

Publications and source records attributed to Wennan Xiong.

9 recordsLinked to original sources
PubMed2005

Characterization of a novel bivalent morphinan possessing kappa agonist and micro agonist/antagonist properties.

Previous research has shown that compounds with mixed kappa and mu activity may have utility for the treatment of cocaine abuse and dependence. The present study characterizes the pharmacological profile of a bivalent morphinan that was shown to be a kappa opioid receptor agonist and a mu opioid receptor agonist/antagonist. MCL-145 [bis(N-cyclobutylmethylmorphinan) fumarate] is related to the morphinan cyclorphan and its N-cyclobutylmethyl derivative MCL-101 [3-hydroxy-N-cyclobutylmethyl morphinan S-(+)-mandelate]. MCL-145 consists of two morphinans connected by a spacer at the 3-hydroxy position. This compound had K(i) values of 0.078 and 0.20 nM for the kappa and mu opioid receptors, respectively, using radioligand binding assays as shown by Neumeyer et al. in 2003. In the guanosine 5'-O -(3-[(35) S]thiotriphosphate) binding assay, MCL-145 produced an E(max) value of 80% for the kappa opioid receptor and 42% for the mu opioid receptor. The EC(50) values obtained for this compound were 4.3 and 3.1 nM for the kappa and mu opioid receptors, respectively. In vivo MCL-145 produced a full dose-response curve in the 55 degrees C warm water tail-flick test and was equipotent to morphine. The agonist properties of MCL-145 were antagonized by the mu-selective antagonist beta-funaltrexamine and the kappa-selective antagonist nor-binaltorphimine. MCL-145 also acted as a mu antagonist, as measured by the inhibition of morphine-induced antinociception.

Analgesics, Opioid↗
PubMed2005

A deoxynucleotide derivatization methodology for improving LC-ESI-MS detection.

We have developed a novel LC-UV-MS derivatization method for the analysis of deoxyguanosine monophosphate adducts that demonstrates enhanced signal intensities relative to underivatized analytes in positive ion mode electrospray ionization MS. Detection of DNA nucleotide adducts is normally conducted in negative ion mode, which requires basic mobile phases that make chromatographic separations difficult and reduce MS sensitivity. Utilizing coupling reagents typically employed in peptide synthesis, several different deoxyguanosine nucleotide phosphoramidates and phosphomonoesters were synthesized in high conversion yield and under mild reaction conditions. The derivatives were characterized by MS/MS and reaction conversion yields determined from the DAD-UV traces. The derivatives were evaluated for ionization efficiencies, fragmentation patterns, and reversed-phase chromatographic properties by LC/ESI-MS/MS. Overall, the hydrophobic derivatives showed increases in ionization efficiency and improved peak shape. Rank ordering of the derivatizing agents was initially established using the dGp-modified derivatives. The best derivatizing agent, hexamethyleneimine, showed a 3-4-fold signal enhancement compared to underivatized dGp and was selected for additional evaluation. A model system using the carcinogen, N-acetoxy-2-acetylaminofluorene (AAAF), was used to synthesize a N-acetyl-(2-aminofluorenyl)-guanosine 5'-monophosphate (dGpAAF) adduct, which was subsequently derivatized with hexamethyleneimine. Detection limits for dGphex and dGpAAFhex, purified by HPLC, were 10- and 3-fold higher (S/N) than their respective underivatized analogues. Practical applicability, with similar improvements in sensitivity, was established by derivatizing adducts isolated from calf thymus DNA exposed to AAAF. Our results demonstrate the utility of simple reactions for the enhanced detection of a mononucleotide in positive ion mode ESI MS and the application of this technique for the detection of dGp-DNA adducts at the low-femtomole level.

Acetoxyacetylaminofluorene↗
PubMed2004

2-aminothiazole-derived opioids. Bioisosteric replacement of phenols.

A series of aminothiazole-derived morphinans, benzomorphans, and morphine were synthesized. Although their affinities were somewhat lower than their phenol prototypes, one compound (9a, ATPM) has been identified possessing high affinity and selectivity at the kappa receptor. Functional assays showed that 9a was a full kappa but partial mu agonist; the efficacy at kappa was significantly greater than at mu receptors. This novel compound may be valuable for the development of long-acting analgesics and drug abuse medication.

Animals↗
PubMed2004

10-Ketomorphinan and 3-substituted-3-desoxymorphinan analogues as mixed kappa and micro opioid ligands: synthesis and biological evaluation of their binding affinity at opioid receptors.

A series of 10-ketomorphinan analogues were synthesized, and their binding affinity at all three opioid receptors was investigated. In most cases, high affinity at micro and kappa receptors, and lower affinity at delta receptor was observed, resulting in good selectivity for micro and kappa receptors. A wide range of substituents can be accommodated on the nitrogen position. The N-(S)-tetrahydrofurfuryl analogue 11 displayed the highest affinity at all three receptors. The N-cyclobutylmethyl analogue 13 gave both high affinity and selectivity at kappa receptor, and N-2-phenylethyl analogue 18 exhibited good affinity and selectivity at micro receptor. Further modifications of the 3-substituent indicated that one H-bond donor was an essential requirement for good affinity at micro and kappa receptors. Similar modifications were investigated at the 3-OH group of morphinans: levorphanol (2a), cyclorphan (2b), and MCL-101 (2c) lacking the 10-keto group. The 3-amino bioisosteric analogues (40 and 41) displayed reasonably good affinity at micro and kappa receptors. The 3-carboxamido replacement (compounds 46-48) in the morphinan subseries resulted in similar affinities comparable to their corresponding 3-OH congeners. The high affinity of these carboxamido analogues, along with their greater lipophilicity and metabolic stability, make them promising candidates for further pharmacological investigation.

Animals↗
PubMed2003

Design and synthesis of novel dimeric morphinan ligands for kappa and micro opioid receptors.

A novel series of morphinans were synthesized, and their binding affinity at and functional selectivity for micro, delta, and kappa opioid receptors were evaluated. These dimeric ligands can be viewed as dimeric morphinans, which were formed by coupling two identical morphinan pharmacophores (cyclorphan (1) or MCL 101 (2)) with varying connecting spacers. Ligands 6 and 7 with alkyl spacers on the nitrogen position and ligands 8 and 9 in which the two morphinan pharmacophores were coupled by ether moieties at the 3-hydroxyl positions showed significant decrease in affinity at all three opioid receptors. An improvement in the affinity was achieved by introducing an ester moiety as the spacer in the dimeric morphinans. It was observed that the affinity of these ligands was sensitive to the character and length of the spacer. Compound 13 (MCL-139) with a 4-carbon ester spacer, compound 17 (MCL-144) containing a 10-carbon spacer, and compound 19 (MCL-145) with the conformationally constrained fumaryl spacer were the most potent ligands in this series, displaying excellent affinities at micro and kappa receptors (K(i) = 0.09-0.2 nM at micro and K(i) = 0.078-0.049 nM at kappa), which were comparable to the parent compound 2. Ligand 12, a compound containing only one morphinan pharmacophore and a long-chain ester group, had affinity at both micro and kappa receptors almost identical to that of the parent ligand 2. In the [(35)S]GTPgammaS binding assay, ligands 13, 17, and 19 and their parent morphinans 1 and 2 stimulated [(35)S]GTPgammaS binding mediated by the micro and kappa receptors. Compounds 13 and 17 were full kappa agonists and partial micro agonists, while compound 19 was a partial agonist at both micro and kappa receptors. These novel ligands, as well as their interesting pharmacological properties, will serve as the basis for our continuing investigation of the dimeric ligands as potential probes for the pharmacotherapy of cocaine abuse and may also open new avenues for the characterization of opioid receptors.

Animals↗
PubMed2002

Zn(ODf)2: preparation and application in asymmetric alkynylation of aldehydes.

A new Lewis acid, Zn(ODf)2, was first prepared from commercially available 3,3,4,4-tetrafluoro[1,2]oxathietane 2,2-dioxide in four steps with 56% yields and also was applied to catalyze highly enantioselective alkynylation of aldehydes in the presence of ligand (1S,2S)-3-(tert-butyldimethylsilyloxyl)-2-N,N-dimethylamino-1- (p-nitrophenyl)-propane-1-ol or ligand (-)-N-methylephedrine to afford the corresponding propargylic alcohols in high yields with up to 99% ee.

Journal Article↗