A concise stereoselective synthesis of (-)-erycibelline.

(-)-Erycibelline, the dihydroxynortropane alkaloid isolated from Erycibe elliptilimba Merr. et Chun., was synthesized using a cyclic nitrone as advanced intermediate, wherein the key step was the SmI(2)-induced intramolecular reductive coupling of cyclic nitrone with aldehyde which resulted in good yield and stereoselectivity.

Synthesis and biological evaluation of bicyclic and tricyclic substituted nortropane derivatives: discovery of a novel selective alpha1D-adrenergic receptor ligand.

A range of 3,6,6-trisubstituted nortropane derivatives based upon 6beta-phenyltropane-3beta,6 alpha-diol have been synthesised from 6beta-hydroxytropinone, including some novel related tricyclic hemi-ketal and tricyclic ketal compounds. Derivatives were assessed for pharmacological affinity and selectivity at alpha(1)-adrenergic receptors, and 6beta-phenyl-8-azabicyclo[3.2.1]octan-3-spiro-2'-(1',3'-dioxolane)-6-ol, a novel lead compound selective for the alpha(1D)-adrenergic receptor, is reported.

Synthesis and evaluation of calystegine B2 analogues as glycosidase inhibitors.

A practical synthesis of polyhydroxylated 6-oxa-nor-tropanes incorporating the essential structural features of calystegine B(2) from 5-deoxy-5-thioureido and 5-ureido-L-idofuranose precursors is presented. The methodology relies on the ability of pseudoamide-type nitrogen atoms (thiourea, urea, and carbamate) to undergo nucleophilic addition to the masked aldehyde group of the monosaccharide. The generated hemiaminal functionality may further undergo in situ intramolecular glycosidation to give the bicyclic aminoacetal compounds, the whole process being favored by the anomeric effect. A series of derivatives bearing different substituents at nitrogen has been prepared and screened against several glycosidases in comparison with xylonojirimycin-type piperidine analogues. Interestingly, strong and highly specific inhibition of bovine liver beta-glucosidase was observed for 6-oxacalystegine B(2) analogues incorporating aromatic pseudoaglyconic groups. On the basis of these data, a 1-azasugar inhibition mode is proposed for this family of glycomimetics.

A selective radiobrominated cocaine analogue for imaging of dopamine uptake sites: pharmacological evaluation and PET experiments.

(E)-N-(3-bromoprop-2-enyl)-2beta-carbomethoxy-3beta-4'-tolyl -nortropane or PE2Br, an analogue of cocaine was labelled with the positron emitter 76Br (T1/2=16 h) for pharmacological evaluation in the rat and PET investigation in the monkey. [76Br]PE2Br was obtained by electrophilic substitution from the tributylstannyl precursor with radiochemical yield of 80%. In vivo biodistribution studies of [76Br]PE2Br (20 MBq/nmol) in rats showed a high uptake in the striatum (2.2% ID/g tissue at 15 min p.i.). The striatum to cerebellum radioactivity ratio was 6 at 1 hour p.i. Striatal uptake of [76Br]PE2Br was almost completely prevented by pretreatment with GBR 12909, but citalopram and maprotiline had no effect, confirming the selectivity of the radioligand for the dopamine transporter. PET imaging of the biodistribution of [76Br]PE2Br in the baboon demonstrated rapid and high uptake in the brain (5% ID at 3 min p.i.). The striatal radioactivity concentration reached a plateau at 20 min p.i. (7% ID/100 mL). The uptake in the cortex and cerebellum was very low. A significantly higher uptake in the thalamus was observed. At 1h p.i., the striatum to cerebellum ratio and thalamus to cerebellum ratio were 8 and 1.9 respectively. In competition experiments the radioactivity in the striatum and the thalamus was displaced by 5 mg/kgof cocaine and 5 mg/kg of GBR 12909, but citalopram and maprotiline had no effect. These results showed that [76Br]PE2Br is in vivo a potent and selective radioligand suitable for PET imagingof the dopamine transporter.