title: Quinolyl analogues of norlobelane: novel potent inhibitors of [(3)H]dihydrotetrabenazine binding and [(3)H]dopamine uptake at the vesicular monoamine transporter-2.
abstract: We have previously shown that quinolyl moieties are attractive structural replacements for the phenyl groups in lobelane. These quinolyl analogues had improved water-solubility over lobelane and retained the potent vesicular monoamine transporter-2 (VMAT-2) inhibitory properties of the parent compound, with quinlobelane (4) exhibiting potent inhibition of uptake at VMAT-2 (Ki=51nM). However, the VMAT-2 inhibitory properties of quinolyl analogues of norlobelane, which is equipotent with lobeline as an inhibitor of [(3)H]dopamine (DA) uptake at VMAT-2, have not been reported. In the current communication, we describe the synthesis of some novel des-methyl quinolyl analogues of lobelane that exhibit greater affinity (Ki=178-647nM) for the dihydrotetrabenazine binding site located on VMAT-2 compared with lobelane (Ki=970nM), norlobelane (Ki=2310nM) and quinlobelane (Ki=2640nM). The most potent compounds, 14 and 15, also exhibited inhibition of [(3)H]DA uptake at VMAT-2 (Ki=42nM) which was comparable to both lobelane (Ki=45nM) and norlobelane (Ki=43nM). Results reveal that binding affinity at VMAT-2 serves as an accurate predictor of inhibition of the function of VMAT-2 for the majority of these analogues. These novel analogues are under consideration for further development as treatments for 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.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Nickell
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Linda P
authors.initials: LP
authors.lastname: Dwoskin
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. Electronic address: pacrooks@uams.edu.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Crooks
mesh_terms: D019969:Amphetamine-Related Disorders / Q000188:drug therapy / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D004298:Dopamine / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008120:Lobeline / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D008694:Methamphetamine / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D013572:Synaptic Vesicles / Q000187:drug effects / Q000378:metabolism; D013747:Tetrabenazine / Q000031:analogs & derivatives* / Q000378:metabolism; D050493:Vesicular Monoamine Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C493454:Slc18a2 protein, rat; D050493:Vesicular Monoamine Transport Proteins; C032811:dihydrotetrabenazine; D008694:Methamphetamine; D008120:Lobeline; D004298:Dopamine; D013747:Tetrabenazine
keywords: Methamphetamine abuse; Quinolyl analogues of norlobelane; VMAT-2; Vesicular [(3)H]dopamine uptake