Graham A. Showell

Binding of 2,4-disubstituted morpholines at human D4 dopamine receptors.

The synthesis of a series of 2,4-disubstituted morpholines is described and their affinities at human dopamine receptors reported. The orally bioavailable 7-azaindole compound 11 has nanomolar affinity at the hD4 receptor with > 1000-fold selectivity over the hD2 receptor.

Design and synthesis of 1,1-disubstituted-1-silacycloalkane-based compound libraries.

The introduction of silicon in biologically-relevant molecules represents an interesting medicinal chemistry tactic. Its use is mainly confined to the fine-tuning of specific molecular properties and organosilicon compounds are underrepresented in typical screening libraries. As part of the European Lead Factory efforts to generate novel, drug discovery-relevant chemical matter, the design and synthesis of 1,1-disubstituted-1-silacycloalkane-based compound libraries is described.

Ester bio-isosteres: synthesis of oxadiazolyl-1-azabicyclo[2.2.1]heptanes as muscarinic agonists

The methyl ester functionality in arecoline and related esters has been replaced by 1,2,4-oxadiazole to generate the most potent and efficacious muscarinic agonists known.

Synthesis, physicochemical and conformational properties of (3R,4R)-3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-1-azabicyclo[2.2.1]heptane, a novel M1 selective muscarinic partial agonist

The cyclopropyloxadiazole derivative described in the title has been shown to be a functionally selective M1 partial agonist with antagonist properties in M2 and M3 muscarinic receptor assays; conformational studies indicate free rotation around the oxadiazole–azanorbornane bond, whilst X-ray studies reveal that the cyclopropyl group is in conjugation with the oxadiazole CN bond.