Lobeline analogs with enhanced affinity and selectivity for plasmalemma and vesicular monoamine transporters

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.