Biomedical subjects

S A Poulsen

Publications and source records attributed to S A Poulsen.

6 recordsLinked to original sources

PubMed2001

High-pressure synthesis of enantiomerically pure C-6 substituted pyrazol.

The synthesis of enantiomerically pure C-6 substituted pyrazolo[3,4-d]pyrimidines has been performed by aromatic nucleophilic substitution of 4-amino-6-chloro-1-phenylpyrazolo[3,4-rd]pyrimidine under conditions of high pressure at ambient temperature. Conventional synthetic conditions (reflux at atmospheric pressure) were unsuccessful. The S enantiomer 11 displayed higher affinity and selectivity for the adenosine A1 receptor than the R enantiomer 12.

Animals↗

PubMed2000

Electrospray ionisation Fourier-transform ion cyclotron resonance mass spectrometry of dynamic combinatorial libraries.

The use of electrospray ionisation Fourier-transform ion cyclotron resonance tandem mass spectrometry (ESI-FTICR-MS/MS) for the analysis of dynamic combinatorial libraries (DCLs) of pseudo-peptide macrocyclic hydrazone oligomers is presented. The design of library building blocks results in mixtures of compounds with greater diversity than libraries generated by conventional combinatorial chemistry and so presents increased demands for analysis. The extended capabilities of the FTICR technique, specifically selective ion trapping, sensitivity, high resolution and mass accuracy over a broad mass range, are compatible with these increased demands and, most importantly, without the need for chromatography. Preliminary studies on the sequencing of cyclic oligomers and confirmation of the presence of sequence isomers are presented. These studies highlight the potential of FTICR-MS as a superior technique for the analysis of combinatorially generated compounds.

Aldehydes↗

PubMed2000

Solution structures in aqueous SDS micelles of two amyloid beta peptides of A beta(1-28) mutated at the alpha-secretase cleavage site (K16E, K16F).

NMRsolution structures are reported for two mutants (K16E, K16F) of the soluble amyloid beta peptide Abeta(1-28). The structural effects of these mutations of a positively charged residue to anionic and hydrophobic residues at the alpha-secretase cleavage site (Lys16-Leu17) were examined in the membrane-simulating solvent aqueous SDS micelles. Overall the three-dimensional structures were similar to that for the native Abeta(1-28) sequence in that they contained an unstructured N-terminus and a helical C-terminus. These structural elements are similar to those seen in the corresponding regions of full-length Abeta peptides Abeta(1-40) and Abeta(1-42), showing that the shorter peptides are valid model systems. The K16E mutation, which might be expected to stabilize the macrodipole of the helix, slightly increased the helix length (residues 13-24) relative to the K16F mutation, which shortened the helix to between residues 16 and 24. The observed sequence-dependent control over conformation in this region provides an insight into possible conformational switching roles of mutations in the amyloid precursor protein from which Abeta peptides are derived. In addition, if conformational transitions from helix to random coil to sheet precede aggregation of Abeta peptides in vivo, as they do in vitro, the conformation-inducing effects of mutations at Lys16 may also influence aggregation and fibril formation.

Amyloid Precursor Protein Secretases↗

PubMed2000

Molecular evolution: dynamic combinatorial libraries, autocatalytic networks and the quest for molecular function.

The principles of Darwinian evolution have been explored in molecular systems such as autocatalytic networks and dynamic combinatorial libraries. Molecular evolution in such systems manifests itself as ligand or receptor amplification by selection. Research efforts exploring these concepts may provide a mechanism for the identification of novel catalysts, molecular receptors and bioactive molecules.

Catalysis↗

PubMed1998

Adenosine receptors: new opportunities for future drugs.

This review summarises current knowledge on adenosine receptors, an important G protein-coupled receptor. The four known adenosine receptor subtypes A1, A2A, A2B, and A3 are discussed with special reference to the opportunities for drug development.

Adenosine↗

PubMed1996

Synthesis and structure-activity relationship of pyrazolo[3,4-d]pyrimidines: potent and selective adenosine A1 receptor antagonists.

A series of 12 substituted 1-phenylpyrazolo[3,4-d]pyrimidines were synthesized and evaluated for rat brain adenosine A1 and A2a receptor binding affinity. Substituents at C-4 and C-6 were varied in order to define these regions in terms of molecular recognition by the receptor subtypes. At C-4, the effects of a mercapto, methylthio, and amino substituent were evaluated, while at C-6, amides with varying alkyl groups extending from the alpha-carbon were examined. This study identified both potent and selective adenosine A1 receptor antagonists. The most potent of the 12 compounds was alpha-[(4-amino-1-phenylpyrazolo[3,4-d]pyrimidin-6-yl)thio]hexanamide (14); with an A1 Ki of 0.939 nM and an A2a Ki of 88.3 nM, this compound is 94-fold A1 selective. The most selective of the 12 compounds was alpha-[[4-(methylthio)-1-phenylpyrazolo[3,4-d]pyrimidin-6-yl]thio]hex anamide (10); with an A1 Ki of 6.81 nM and an A2a Ki > 40 000 nM, this compound is > 5900-fold A1 selective. The structure-activity relationships for the complete series has identified discrete structural differences between the A1 and A2a receptors with respect to the binding of pyrazolo[3,4-d]pyrimidines. This study resulted in prediction that increased A1 affinity could be achieved by incorporation of NH-alkyl substituents at C-4. This was confirmed by synthesis of alpha-[[4-(methylamino)-1-phenylpyrazolo[3,4-d]pyrimidin-6-yl]thiol] hexanamide (15) which was found to have an A1 Ki of 0.745 nM.

Adenosine↗