Loading…

The Novel Pyrrolidine Nor-Lobelane Analog UKCP-110 [cis-2,5-di-(2-phenethyl)-pyrrolidine hydrochloride] Inhibits VMAT2 Function, Methamphetamine-Evoked Dopamine Release, and Methamphetamine Self-Administration in RatsS

Both lobeline and lobelane attenuate methamphetamine self-administration in rats by decreasing methamphetamine-induced dopamine release via interaction with vesicular monoamine transporter-2 (VMAT2). A novel derivative of nor-lobelane, cis -2,5-di-(2-phenethyl)-pyrrolidine hydrochloride (UKCP-110),...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of pharmacology and experimental therapeutics 2010-12, Vol.335 (3), p.841-851
Main Authors: Beckmann, Joshua S., Siripurapu, Kiran B., Nickell, Justin R., Horton, David B., Denehy, Emily D., Vartak, Ashish, Crooks, Peter A., Dwoskin, Linda P., Bardo, Michael T.
Format: Article
Language:English
Subjects:
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Both lobeline and lobelane attenuate methamphetamine self-administration in rats by decreasing methamphetamine-induced dopamine release via interaction with vesicular monoamine transporter-2 (VMAT2). A novel derivative of nor-lobelane, cis -2,5-di-(2-phenethyl)-pyrrolidine hydrochloride (UKCP-110), and its trans -isomers, (2 R ,5 R )- trans -di-(2-phenethyl)-pyrrolidine hydrochloride (UKCP-111) and (2 S ,5 S )- trans -di-(2-phenethyl)-pyrrolidine hydrochloride (UKCP-112), were evaluated for inhibition of [ 3 H]dihydrotetrabenazine binding and [ 3 H]dopamine uptake by using a rat synaptic vesicle preparation to assess VMAT2 interaction. Compounds were evaluated for inhibition of [ 3 H]nicotine and [ 3 H]methyllycaconitine binding to assess interaction with the major nicotinic receptor subtypes. In addition, compounds were evaluated for inhibition of methamphetamine-evoked endogenous dopamine release by using striatal slices. The most promising compound, UKCP-110, was evaluated for its ability to decrease methamphetamine self-administration and methamphetamine discriminative stimulus cues and for its effect on food-maintained operant responding. UKCP-110, UKCP-111, and UKCP-112 inhibited [ 3 H]dihydrotetrabenazine binding ( K i = 2.66 ± 0.37, 1.05 ± 0.10, and 3.80 ± 0.31 μM, respectively) and had high potency inhibiting [ 3 H]dopamine uptake ( K i = 0.028 ± 0.001, 0.046 ± 0.008, 0.043 ± 0.004 μM, respectively), but lacked affinity at nicotinic receptors. Although the trans -isomers did not alter methamphetamine-evoked dopamine release, UKCP-110 inhibited (IC 50 = 1.8 ± 0.2 μM; I max = 67.18 ± 6.11 μM) methamphetamine-evoked dopamine release. At high concentrations, UKCP-110 also increased extracellular dihydroxyphenylacetic acid. It is noteworthy that UKCP-110 decreased the number of methamphetamine self-infusions, while having no effect on food-reinforced behavior or the methamphetamine stimulus cue. Thus, UKCP-110 represents a new lead in the development of novel pharmacotherapies for the treatment of methamphetamine abuse.
ISSN:0022-3565
1521-0103
DOI:10.1124/jpet.110.172742