Lobeline and structurally simplified analogs exhibit differential agonist activity and sensitivity to antagonist blockade when compared to nicotine

Terry, Alvin V.; Williamson, Richard A.; Gattu, Mahanandeeshwar; Beach, Joseph Warren; McCurdy, C. R.; Sparks, J A; Pauly, James R.

doi:10.1016/s0028-3908(97)00142-1

Cited by 41 publications

(25 citation statements)

References 32 publications

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“…Therefore, the compound does not appear to express its behavioral effects through nAChr mechanisms (at least via the α 4 β 2 subtype). The binding results with nicotine in rodent brain are in general agreement with the data presented by our group previously [Terry et al, 1998] and by other investigators [Reavill et al, 1988;Grady et al, 1992].…”

Section: Discussionsupporting

confidence: 92%

Ranitidine analog, JWS-USC-75IX, enhances memory-related task performance in rats

et al. 1999

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Section: Discussionsupporting

confidence: 92%

Ranitidine analog, JWS-USC-75IX, enhances memory-related task performance in rats

et al. 1999

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“…For example, it fails to block several actions of lobeline in behavioral [Terry et al, 1996] and neurochemical [Clarke and Reuben, 1996;Terry et al, 1998b] studies, fails (at 1.0 mg/kg) to block the enhanced effect of ABT-418 on DSDT , and fails to antagonize the antinociceptive effects of some isoarecolone analogs [Beach et al, 1998]. Furthermore, the antinociceptive effects elicited by intrathecal administration of the nicotinic ligands DMPP, N-MCC, N-MNP, lobeline, and (+)-BN were not blocked by mec .…”

Section: Response Latenciesmentioning

confidence: 99%

Dose‐specific improvements in memory‐related task performance by rats and aged monkeys administered the nicotinic‐cholinergic antagonist mecamylamine

Terry

Buccafusco

Prendergast

1999

Drug Development Research

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“…3 H]cytisine binding to rat cortical membranes and stimulation of 86 Rb ϩ efflux from striatal synaptosomes (Terry et al, 1998). Lobeline fragments, containing either the phenylcarboxymethylene or phenylhydroxyethylene moiety, were less potent than lobeline at ␣4␤2* nAChRs, indicating the importance of these moieties for optimal affinity at ␣4␤2* (Flammia et al, 1999).…”

mentioning

confidence: 95%

Lobelane Inhibits Methamphetamine-Evoked Dopamine Release via Inhibition of the Vesicular Monoamine Transporter-2

Nickell¹,

Krishnamurthy²,

Norrholm³

et al. 2009

J Pharmacol Exp Ther

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Lobeline is currently being evaluated in clinical trials as a methamphetamine abuse treatment. Lobeline interacts with nicotinic receptor subtypes, dopamine transporters (DATs), and vesicular monoamine transporters (VMAT2s). Methamphetamine inhibits VMAT2 and promotes dopamine (DA) release from synaptic vesicles, resulting ultimately in increased extracellular DA. The present study generated structure-activity relationships by defunctionalizing the lobeline molecule and determining effects on [ H]dihydrotetrabenazine binding, inhibition of [3 H]DA uptake into striatal synaptic vesicles and synaptosomes, the mechanism of VMAT2 inhibition, and inhibition of methamphetamine-evoked DA release. Compared with lobeline, the analogs exhibited greater potency inhibiting DA transporter (DAT) function. Saturated analogs, lobelane and nor-lobelane, exhibited high potency (K i ϭ 45 nM) inhibiting vesicular [ 3 H]DA uptake, and lobelane competitively inhibited VMAT2 function. Lobeline and lobelane exhibited 67-and 35-fold greater potency, respectively, in inhibiting VMAT2 function compared to DAT function. Lobelane potently decreased (IC 50 ϭ 0.65 M; I max ϭ 73%) methamphetamine-evoked DA overflow, and with a greater maximal effect compared with lobeline (IC 50 ϭ 0.42 M, I max ϭ 56.1%). These results provide support for VMAT2 as a target for inhibition of methamphetamine effects. Both transisomers and demethylated analogs of lobelane had reduced or unaltered potency inhibiting VMAT2 function and lower maximal inhibition of methamphetamine-evoked DA release compared with lobelane. Thus, defunctionalization, cis-stereochemistry of the side chains, and presence of the piperidino N-methyl are structural features that afford greatest inhibition of methamphetamine-evoked DA release and enhancement of selectivity for VMAT2. The current results reveal that lobelane, a selective VMAT2 inhibitor, inhibits methamphetamine-evoked DA release and is a promising lead for the development of a pharmacotherapeutic for methamphetamine abuse.

show abstract

Lobeline and structurally simplified analogs exhibit differential agonist activity and sensitivity to antagonist blockade when compared to nicotine

Cited by 41 publications

References 32 publications

Ranitidine analog, JWS-USC-75IX, enhances memory-related task performance in rats

Ranitidine analog, JWS-USC-75IX, enhances memory-related task performance in rats

Dose‐specific improvements in memory‐related task performance by rats and aged monkeys administered the nicotinic‐cholinergic antagonist mecamylamine

Lobelane Inhibits Methamphetamine-Evoked Dopamine Release via Inhibition of the Vesicular Monoamine Transporter-2

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