Behavioural and pharmacokinetic studies on nicotine, cytisine and lobeline

Reavill, C.; Walther, Bernard; Stolerman, I. P.; Testa, Bernard

doi:10.1016/0028-3908(90)90022-j

Cited by 134 publications

(77 citation statements)

References 18 publications

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“…As previously reported, lobeline has high affinity for [ 3 H]nicotine binding sites in rodent striatal membrane preparations (K i ϭ 4 -20 nM) (Abood et al, 1988;Reavill et al, 1990;Bhat et al, 1991;Court et al, 1994;Flammia et al, 1999). Defunctionalized lobeline analogs lobelane, MTD, and (Ϫ)-TTD generally exhibited decreased affinity for [ Lobeline Analog Pharmacology 1041 the ‫ء2␤4␣‬ site, indicating that stereochemical factors play a role in binding site recognition.…”

Section: Discussionsupporting

confidence: 52%

“…Until recently, the pharmacological activity of lobeline was believed to primarily result from its high-affinity (K i ϭ 4-20 nM) interaction with nicotinic acetylcholine receptors (nAChRs) (Abood et al, 1988;Reavill et al, 1990;Bhat et al, 1991;Court et al, 1994). Lobeline inhibits nAChR subtypes mediating both nicotine-evoked [ 3 H]DA release and nicotineevoked 86 Rb ϩ efflux (Miller et al, 2000); however, lobeline also interacts with VMAT2 and DAT (Dwoskin and Crooks, 2002).…”

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confidence: 99%

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Lobeline Analogs with Enhanced Affinity and Selectivity for Plasmalemma and Vesicular Monoamine Transporters

Miller¹,

Crooks²,

Zheng³

et al. 2004

J Pharmacol Exp Ther

107

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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 [ 3 H]methyllycaconitine binding site ‫ء7␣(‬ nAChR subtype). Lobeline tosylate was equipotent with lobeline in inhibiting [3 H]nicotine binding but 70-fold more potent in inhibiting nicotine-evoked 86 Rb ϩ efflux, demonstrating antagonism of ‫ء2␤4␣‬ nAChRs. Compared with lobeline, the defunctionalized analogs lobelane, mesotransdiene, and (Ϫ)-trans-transdiene showed dramatically reduced affinity at ‫ء2␤4␣‬ nAChRs and a 15-to 100-fold higher affinity (K i ϭ 1.95, 0.58, and 0.26 M, respectively) at DATs. Mesotransdiene and (Ϫ)-transtransdiene 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 (K i ϭ 0.01 and 0.04 M, respectively) than lobeline in inhibiting [3 H]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 (K i ϭ 0.92 and 1.35 M, respectively) than lobeline (K i ϭ 5.46 M) in inhibiting [ 3 H]methoxytetrabenazine binding to VMAT2 in vesicle preparations. Thus, structural modification (defunctionalization) of the lobeline molecule markedly decreases affinity for ‫ء2␤4␣‬ and ‫ء7␣‬ 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.Lobeline, an alkaloid from Indian tobacco, inhibits the behavioral and neurochemical effects of psychostimulant drugs of abuse. For example, lobeline attenuates d-amphetamine-, methamphetamine-and nicotine-induced hyperactivity (Green et al., 2001;Miller et al., 2001Miller et al., , 2002 and inhibits the discriminative stimulus effects of methamphetamine ). Although lobeline is not selfadministered, it decreases methamphetamine self-administration in rats, which is not surmounted by increasing methamphetamine unit doses (Harrod et al., , 2003. These results suggest that lobeline lacks abuse liability while decreasing the stimulant and rewarding effects of methamphetamine via a noncompetitive mechanism of action.Psychostimulant-induced behavioral activation and reinforcement are at least partly mediated via interaction with neurotransmitter transporters that r...

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Section: Discussionsupporting

confidence: 52%

mentioning

confidence: 99%

Lobeline Analogs with Enhanced Affinity and Selectivity for Plasmalemma and Vesicular Monoamine Transporters

Miller¹,

Crooks²,

Zheng³

et al. 2004

J Pharmacol Exp Ther

107

View full text Add to dashboard Cite

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“…Lobeline has been shown to interact with high affinity at the [³H] nicotine binding site, indicating that it has high affinity for α4β2* nicotinic acetylcholine receptors (Abood et al, 1989;Damaj et al, 1997;Miller et al, 2000). Behavioral and pharmacological evidence suggests that lobeline functions as a nicotinic acetylcholine receptor antagonist (Benwell and Balfour, 1998;Miller et al, 2000;Reavill et al, 1990). In particular, lobeline inhibits nicotine-evoked 86 Rb + efflux from rat thalamic synaptosomes and nicotineevoked [³H]dopamine overflow from rat striatal slices preloaded with [³H]dopamine, suggesting it acts functionally as an antagonist at α4β2* and α6-containing nicotinic acetylcholine receptors (Miller et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Lobelane decreases methamphetamine self-administration in rats

Neugebauer

Harrod

Stairs

et al. 2007

European Journal of Pharmacology

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Lobelane, a minor alkaloid of Lobelia inflata and a synthetic, des-oxy analog of lobeline, has good affinity for the vesicular monoamine transporter and the dopamine transporter. The current study examined the ability of lobelane to specifically decrease methamphetamine self-administration. Rats were trained on a fixed ratio 5 schedule of reinforcement to self-administer methamphetamine (0.05 mg/kg/infusion, i.v.) or to respond for sucrose pellets. Upon reaching stable responding, rats were pretreated with lobelane (0.1, 1, 3, 5.6, or 10 mg/kg, s.c.) or saline, 15 min prior to the operant session. To assess the effect of repeated lobelane on methamphetamine self-administration, rats were pretreated with lobelane (5.6 or 10 mg/kg, s.c.) for 7 sessions. Behavioral specificity was further investigated by assessing the effects of lobelane (0.1, 1, 3, 5, or 10 mg/kg, s.c.) or saline on locomotor activity. Within the dose range tested, lobelane dose-dependently decreased methamphetamine selfadministration, while having no effect on sucrose-maintained responding. Locomotor activity was decreased following only the highest dose of lobelane (10 mg/kg). Across repeated pretreatments, tolerance developed to the effect of lobelane on methamphetamine self-administration, demonstrating that the ability of lobelane to specifically decrease methamphetamine selfadministration is a transient effect. Thus, taken together, the results show that although lobelane interacts with the pharmacological targets believed to be responsible for its ability to decrease methamphetamine self-administration, removal of the oxygen functionalities from the lobeline molecule may have afforded a compound with an altered pharmacokinetic and/or pharmacodynamic profile.

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“…In early smoking-cessation studies, cytisine failed to exhibit efficacy (Benndorf, Scharfenberg, Kempe, Wendekamm, & Winkelvoss, 1970;Scharfenberg, Benndorf, & Kempe, 1971), but more recent clinical trials in eastern Europe suggest that cytisine (Tabex) may indeed promote smoking cessation (Etter, 2006). The reduced therapeutic efficacy of cytisine compared with varenicline may be attributed to its poorer absorption and brain penetration properties (Barlow & McLeod, 1969;Reavill, Walther, Stolerman, & Testa, 1990). Similarly, the α4β2* nAChR partial agonist dianicline (SSR-591,813), developed by SanofiAventis for smoking cessation, is less efficacious than varenicline likely because of its poorer brain penetration properties ).…”

Section: Nicotinic Acetylcholine Receptors and Smoking Cessationmentioning

confidence: 99%