Pieter A. M. van der Klein

Elucidation of structure-activity relationships of 2-amino-3-benzoylthiophenes : Study of their allosteric enhancing vs. antagonistic activity on adenosine A1 receptors

Novel 2‐amino‐3‐benzoylthiophene derivatives, with variable substitution on the thiophene as well as benzoyl ring, were synthesized and evaluated both as allosteric enhancers of agonist binding to the rat adenosine A1 receptor, and as antagonists on this receptor. Structural features were identified on the novel derivatives that favored allosteric enhancing activity, such as benzoyl lipophilic substitution and thiophene 4‐alkyl substitution. In contrast, antagonistic properties were favored by thiophene 5‐bulky substitution. Upon further analysis, a significant correlation was found between antagonistic activity and hydrophobic fragment constants (π values) of substituent R5, in contrast to a negative correlation with those of R4. Comparison of low energy conformations of some of the 2‐amino‐3‐benzoylthiophene derivatives (PD81,723 and 4f) with known adenosine A1 antagonists (theophylline and 8‐cyclohexyltheophylline) indicated that thiophene 5‐substituents may interact with the same lipophilic domain of the adenosine A1 receptor accommodating 8‐substituents of xanthine antagonists. Drug Dev. Res. 49:227–237, 2000.

Application of cyclic sulfates in the synthesis of 6-deoxy-d-manno-heptopyranose derivatives

Abstract 6-Deoxy- d -manno-heptopyranose was prepared in five steps starting from methyl 2,3-O-isopropylidene-α- d -mannopyranoside 4,6-sulfate or methyl 2,3-O-isopropylidene-α- d -mannofuranoside 5,6-sulfate. The glycosyl donor ethyl 2,3,4,7-tetra-O-benzoyl-6-deoxyl-1-thio-α,β- d -manno-heptopyranoside was used to synthesise methyl 4-O-(6-deoxy-α- d -manno-heptopyranosyl)-β- d -galactopyranoside.

Phenyl-substituted N6-phenyladenosines and N6-phenyl-5′-N-ethylcarboxamidoadenosines with high activity at human adenosine A2B receptors

A series of phenyl‐substituted N6‐phenyladenosines and N6‐phenyl‐5′‐N‐ethylcarboxamidoadenosines were synthesized and tested at adenosine receptor subtypes. EC50 values were determined for cyclic AMP production in CHO cells expressing human A2B receptors. Binding affinities were determined for rat A1 and A2A receptors and human A3 receptors. N6‐phenyladenosine displayed an EC50 value at A2B receptors of 6.3 μM. Several N6‐phenyladenosine derivatives were more active than N6‐phenyladenosine, while two analogs were also more potent than 5′‐N‐ethylcarboxamidoadenosine (NECA, 0.76 μM), i.e., the 4‐iodophenyl (10, 0.37 μM) and the 4‐aminosulfonylphenyl (20, 0.44 μM) derivatives. N6‐phenyl‐NECA derivatives were as active as their analogous adenosine derivatives. Drug Dev. Res. 49:85–93, 2000.

A Cyclic Sulfate Approach to the Synthesis of 1,4-Dideoxy-1,4-imino Derivatives of L-Xylitol, L-Arabinitol and D-Xylitol

Abstract Polyhydroxylated pyrrolidines are readily accessible by ring opening of a 1,4-cyclic sulfate function in pentitol derivatives by nitrogen nucleophiles and further processing of the in situ generated charged sulfate group.

Allosteric modulation of G protein-coupled receptors.

Allosteric modulation of G protein-coupled receptors has recently been recognized as an alternative approach for selectivity in drug action. Allosteric modulators that enhance or diminish the effects of (endogenous) agonists or antagonists on a variety of G protein-coupled receptors are described in this review, with emphasis on the latest developments in this research area. Specific examples include allosteric ligands for adenosine A1 and A3 receptors, Ca(2+)-sensing receptors, metabotropic glutamate receptor subtypes, gamma-aminobutyric acid type B and muscarinic receptors. It appears that all three major classes of G protein-coupled receptors (A, B and C) are amenable to allosteric modulation by small molecules. This constitutes an attractive and novel means to identify new leads in the drug discovery process. However, it requires a reengineering of most current assays.

An expeditious liquid-phase synthesis of cyclic peptide nucleic acids

Abstract Suitably protected linear precursors of cyclic PNAs can be readily obtained by BOP/DiPEA coupling of the corresponding sub-monomers. Conversion of the linear PNA dimers into the pentafluorophenyl esters allows cyclization by intramolecular attack of the deprotected primary amino function under diluted conditions. After removal of the secondary amino protecting group(s), installation of the required nucleobase-acetyl function(s) affords cyclic PNAs. In addition, the latter compounds can be prepared following a direct coupling strategy.