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Synthesis and evaluation of novel azetidine analogs as potent inhibitors of vesicular [3H]dopamine uptake.

ABSTRACT: Lobelane analogs that incorporate a central piperidine or pyrrolidine moiety have previously been reported by our group as potent inhibitors of VMAT2 function. Further central ring size reduction of the piperidine moiety in lobelane to a four-membered heterocyclic ring has been carried out in the current study to afford novel cis-and trans-azetidine analogs. These azetidine analogs (15a-15c and 22a-22c) potently inhibited [(3)H]dopamine (DA) uptake into isolated synaptic vesicles (Ki?66nM). The cis-4-methoxy analog 22b was the most potent inhibitor (Ki=24nM), and was twofold more potent that either lobelane (2a, Ki=45nM) or norlobelane (2b, Ki=43nM). The trans-methylenedioxy analog, 15c (Ki=31nM), was equipotent with the cis-analog, 22b, in this assay. Thus, cis- and trans-azetidine analogs 22b and 15c represent potential leads in the discovery of new clinical candidates for the treatment of methamphetamine abuse.

SUBMITTER: Ding D 

PROVIDER: S-EPMC3914663 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Synthesis and evaluation of novel azetidine analogs as potent inhibitors of vesicular [3H]dopamine uptake.

Ding Derong D   Nickell Justin R JR   Deaciuc Agripina G AG   Penthala Narsimha Reddy NR   Dwoskin Linda P LP   Crooks Peter A PA  

Bioorganic & medicinal chemistry 20130811 21

Lobelane analogs that incorporate a central piperidine or pyrrolidine moiety have previously been reported by our group as potent inhibitors of VMAT2 function. Further central ring size reduction of the piperidine moiety in lobelane to a four-membered heterocyclic ring has been carried out in the current study to afford novel cis-and trans-azetidine analogs. These azetidine analogs (15a-15c and 22a-22c) potently inhibited [(3)H]dopamine (DA) uptake into isolated synaptic vesicles (Ki⩽66nM). The  ...[more]

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