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-(2-phenethyl)-pyrrolidine hydrochloride (UKCP-110) and its trans-isomers, (2R,5R)-trans-di-(2-phenethyl)-pyrrolidine hydrochloride (UKCP-111) and (2S,5S)-trans-di-(2-phenethyl)-pyrrolidine hydrochloride (UKCP-112) were evaluated for inhibition of [3H]dihydrotetrabenazine binding and [3H]dopamine uptake using a rat synaptic vesicle preparation to assess VMAT2 interaction. Compounds were evaluated for inhibition of [3H]nicotine and [3H]methyllycaconitine binding to assess interaction with the major nicotinic receptor subtypes. Also, compounds were evaluated for inhibition of methamphetamine-evoked 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 [3H]dihydrotetrabenazine binding [Ki = 2.66 ± 0.37 µM, 1.05 ± 0.10 µM, 3.80 ±0.31 µM, respectively], and had high potency inhibiting [3H]dopamine uptake [Ki = 0.028 ± 0.001 µ;M, 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, UKCP-110 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.
- Received July 13, 2010.
- Revision received August 16, 2010.
- Accepted August 19, 2010.
- The American Society for Pharmacology and Experimental Therapeutics