title: Lobeline analogs with enhanced affinity and selectivity for plasmalemma and vesicular monoamine transporters.
abstract: Lobeline attenuates the behavioral effects of psychostimulants in rodents and inhibits the function of nicotinic receptors (nAChRs), dopamine transporters (DATs), and vesicular monoamine transporters (VMAT2s). Monoamine transporters are considered valid targets for drug development for the treatment of methamphetamine abuse. In the current study, a series of lobeline analogs were evaluated for affinity and selectivity at these targets. None of the analogs was more potent than nicotine at the [3H]methyllycaconitine binding site (alpha7* nAChR subtype). Lobeline tosylate was equipotent with lobeline in inhibiting [3H]nicotine binding but 70-fold more potent in inhibiting nicotine-evoked 86Rb+ efflux, demonstrating antagonism of alpha4beta2* nAChRs. Compared with lobeline, the defunctionalized analogs lobelane, mesotransdiene, and (-)-trans-transdiene showed dramatically reduced affinity at alpha4beta2* nAChRs and a 15- to 100-fold higher affinity (Ki = 1.95, 0.58, and 0.26 microM, respectively) at DATs. Mesotransdiene and (-)-trans-transdiene competitively inhibited DAT function, whereas lobelane and lobeline acted noncompetitively. 10S/10R-MEPP [N-methyl-2R-(2R/2S-hydroxy-2-phenylethyl)6S-(2-phenylethyl)piperidine] and 10R-MESP [N-methyl-2R-(2R-hydroxy-2-phenylethyl)6S-(2-phenylethen-1-yl)piperidine] were 2 to 3 orders of magnitude more potent (Ki = 0.01 and 0.04 microM, respectively) than lobeline in inhibiting [3H]serotonin uptake; 10S/10R-MEPP showed a 600-fold selectivity for this transporter. Uptake results using hDATs and human serotonin transporters expressed in human embryonic kidney-293 cells were consistent with native transporter assays. Lobelane and ketoalkene were 5-fold more potent (Ki = 0.92 and 1.35 microM, respectively) than lobeline (Ki = 5.46 microM) in inhibiting [3H]methoxytetrabenazine binding to VMAT2 in vesicle preparations. Thus, structural modification (defunctionalization) of the lobeline molecule markedly decreases affinity for alpha4beta2* and alpha7* nAChRs while increasing affinity for neurotransmitter transporters, affording analogs with enhanced selectivity for these transporters and providing new leads for the treatment of psychostimulant abuse.
authors.affiliation: College of Pharmacy, University of Kentucky, Lexington, KY, 40536-0082, USA.
authors.forename: Dennis K
authors.initials: DK
authors.lastname: Miller
authors.forename: Peter A
authors.initials: PA
authors.lastname: Crooks
authors.forename: Guangrong
authors.initials: G
authors.lastname: Zheng
authors.forename: Vladimir P
authors.initials: VP
authors.lastname: Grinevich
authors.forename: Seth D
authors.initials: SD
authors.lastname: Norrholm
authors.forename: Linda P
authors.initials: LP
authors.lastname: Dwoskin
mesh_terms: D000157:Aconitine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D003042:Cocaine / Q000031:analogs & derivatives / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D005731:Ganglionic Stimulants / Q000494:pharmacology; D006801:Humans; D007457:Iodine Radioisotopes; D007700:Kinetics; D008120:Lobeline / Q000031:analogs & derivatives / Q000494:pharmacology*; D008297:Male; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009479:Neuropeptides; D009538:Nicotine / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D012413:Rubidium / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins; D027981:Symporters / Q000378:metabolism; D013747:Tetrabenazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014316:Tritium; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins
chemical_list: D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D005731:Ganglionic Stimulants; D007457:Iodine Radioisotopes; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D050484:Norepinephrine Plasma Membrane Transport Proteins; C493452:SLC18A2 protein, human; C493227:SLC6A2 protein, human; C493214:SLC6A3 protein, human; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; C493454:Slc18a2 protein, rat; C493226:Slc6a2 protein, rat; C493216:Slc6a3 protein, rat; C493232:Slc6a4 protein, rat; D027981:Symporters; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; D014316:Tritium; C084867:5-O-methyldihydrotetrabenazine; C054634:methyllycaconitine; D012701:Serotonin; C069723:2beta-carbomethoxy-3beta-(4-iodophenyl)tropane; D009538:Nicotine; D008120:Lobeline; D003042:Cocaine; D012413:Rubidium; D004298:Dopamine; D009638:Norepinephrine; D000157:Aconitine; D013747:Tetrabenazine