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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),...
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Published in: | The Journal of pharmacology and experimental therapeutics 2010-12, Vol.335 (3), p.841-851 |
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Main Authors: | , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Online Access: | Get full text |
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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. |
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ISSN: | 0022-3565 1521-0103 |
DOI: | 10.1124/jpet.110.172742 |