title: 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.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Derong
authors.initials: D
authors.lastname: Ding
authors.forename: Justin R
authors.initials: JR
authors.lastname: Nickell
authors.forename: Agripina G
authors.initials: AG
authors.lastname: Deaciuc
authors.forename: Narsimha Reddy
authors.initials: NR
authors.lastname: Penthala
authors.forename: Linda P
authors.initials: LP
authors.lastname: Dwoskin
authors.forename: Peter A
authors.initials: PA
authors.lastname: Crooks
mesh_terms: D000818:Animals; D001384:Azetidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D007536:Isomerism; D007700:Kinetics; D008120:Lobeline / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D013572:Synaptic Vesicles / Q000378:metabolism; D014316:Tritium / Q000737:chemistry; D050493:Vesicular Monoamine Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D001384:Azetidines; D018765:Dopamine Uptake Inhibitors; C493454:Slc18a2 protein, rat; D050493:Vesicular Monoamine Transport Proteins; C540157:lobelane; D014316:Tritium; C082735:azetidine; D008120:Lobeline; D004298:Dopamine
keywords: Azetidine analogs; Lobelane; Methamphetamine abuse; VMAT2; [(3)H]DA uptake