JPET #172742 1 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 Rats

Both lobeline and lobelane attenuate methamphetamine self-administration in rats by decreasing methamphetamine-induced dopamine release via interaction with the vesicular monoamine transporter-2 (VMAT2). A novel derivative of nor-lobelane, cis-2,5-di-(2phenethyl)-pyrrolidine hydrochloride (UKCP-110) and its trans-isomers, (2R,5R)-trans-di-(2phenethyl)-pyrrolidine hydrochloride (UKCP-111) and (2S,5S)-trans-di-(2-phenethyl)pyrrolidine hydrochloride (UKCP-112) were evaluated for inhibition of [H]dihydrotetrabenazine binding and [H]dopamine uptake using a rat synaptic vesicle preparation to assess VMAT2 interaction. Compounds were evaluated for inhibition of [H]nicotine and [H]methyllycaconitine binding to assess interaction with the major nicotinic receptor subtypes. Also, compounds were evaluated for inhibition of methamphetamineevoked endogenous dopamine release 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 [H]dihydrotetrabenazine binding [Ki = 2.66 ± 0.37 μM, 1.05 ± 0.10 μM, 3.80 ± 0.31 μM, respectively], and had high potency inhibiting [H]dopamine uptake [Ki = 0.028 ± 0.001 μM, 0.046 ± 0.008 μM, 0.043 ± 0.004 μM, respectively], but lacked affinity at nicotinic receptors. While the trans-isomers did not alter methamphetamine-evoked dopamine release, UKCP110 inhibited [IC50 = 1.8 ± 0.2 μM; Imax = 67.18 ± 6.11 μM] methamphetamine-evoked dopamine release. At high concentrations, UKCP-110 also increased extracellular dihydroxyphenylacetic acid. Importantly, 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. This article has not been copyedited and formatted. The final version may differ from this version. JPET Fast Forward. Published on August 30, 2010 as DOI: 10.1124/jpet.110.172742 at A PE T Jornals on Jauary 9, 2018 jpet.asjournals.org D ow nladed from