Novel N-1,2-Dihydroxypropyl Analogs of Lobelane Inhibit Vesicular Monoamine Transporter-2 Function and Methamphetamine-Evoked Dopamine Release

David B. Horton; Kiran B. Siripurapu; Guangrong Zheng; Peter A. Crooks; Linda P. Dwoskin

doi:10.1124/jpet.111.184770

Abstract

Lobelane, a chemically defunctionalized saturated analog of lobeline, has increased selectivity for the vesicular monoamine transporter 2 (VMAT2) compared with the parent compound. Lobelane inhibits methamphetamine-evoked dopamine (DA) release and decreases methamphetamine self-administration. Unfortunately, tolerance develops to the ability of lobelane to decrease these behavioral effects of methamphetamine. Lobelane has low water solubility, which is problematic for drug development. The aim of the current study was to determine the pharmacological effect of replacement of the N-methyl moiety with a chiral N-1,2-dihydroxypropyl (N-1,2-diol) moiety, which enhances water solubility, altering the configuration of the N-1,2-diol moiety and incorporating phenyl ring substituents into the analogs. To determine VMAT2 selectivity, structure-activity relationships also were generated for inhibition of DA and serotonin transporters. Analogs with the highest potency for inhibiting DA uptake at VMAT2 and at least 10-fold selectivity were evaluated further for ability to inhibit methamphetamine-evoked DA release from superfused striatal slices. (R)-3-[2,6-cis-di(4-methoxyphenethyl)piperidin-1-yl]propane-1,2-diol (GZ-793A), the (R)-4-methoxyphenyl-N-1,2-diol analog, and (R)-3-[2,6-cis-di(1-naphthylethyl)piperidin-1-yl]propane-1,2-diol (GZ-794A), the (R)-1-naphthyl-N-1,2-diol analog, exhibited the highest potency (K_i ∼30 nM) inhibiting VMAT2, and both analogs inhibited methamphetamine-evoked endogenous DA release (IC₅₀ = 10.6 and 0.4 μM, respectively). Thus, the pharmacophore for VMAT2 inhibition accommodates the N-1,2-diol moiety, which improves drug-likeness and enhances the potential for the development of these clinical candidates as treatments for methamphetamine abuse.

Footnotes

This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grants DA13519, DA016176].
The University of Kentucky holds patents on lobeline and the analogs described in the current work, which have been licensed by Yaupon Therapeutics, Inc. A potential royalty stream to D.B.H., G.Z., P.A.C., and L.P.D. may occur consistent with University of Kentucky policy. Both P.A.C. and L.P.D. are founders of, and have financial interest in, Yaupon Therapeutics, Inc.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

doi:10.1124/jpet.111.184770.
ABBREVIATIONS:
DAT
dopamine transporter
5-HT
5-hydroxytryptamine (serotonin)
ANOVA
analysis of variance
DA
dopamine
DTBZ
dihydrotetrabenazine
EC
electrochemical detection
GBR 12909
1-(2-(bis-(4-fluorophenyl)methoxy)ethyl)-4-(3-phenylpropyl)piperazine
GZ-252C
para-methoxyphenyl lobelane
GZ-745A
(R)-3-(2,6-cis-diphenethylpiperidin-1-yl)propane-1,2-diol
GZ-745B
(S)-3-(2,6-cis-diphenethylpiperidin-1-yl)propane-1,2-diol
GZ-790A
(R)-3-[2,6-cis-di(3-methoxyphenethyl)piperidin-1-yl]propane-1,2-diol
GZ-790B
(S)-3-[2,6-cis-di(3-methoxyphenethyl)piperidin-1-yl]propane-1,2-diol
GZ-791A
(R)-3-[2,6-cis-di(3-fluorophenethyl)piperidin-1-yl]propane-1,2-diol
GZ-791B
(S)-3-[2,6-cis-di(3-fluorophenethyl)piperidin-1-yl]propane-1,2-diol
GZ-792A
(R)-3-[2,6-cis-di(2-methoxyphenethyl)piperidin-1-yl]propane-1,2-diol
GZ-792B
(S)-3-[2,6-cis-di(2-methoxyphenethyl)piperidin-1-yl]propane-1,2-diol
GZ-793A
(R)-3-[2,6-cis-di(4-methoxyphenethyl)piperidin-1-yl]propane-1,2-diol
GZ-793B
(S)-3-[2,6-cis-di(4-methoxyphenethyl)piperidin-1-yl]propane-1,2-diol
GZ-794A
(R)-3-[2,6-cis-di(1-naphthylethyl)piperidin-1-yl]propane-1,2-diol
GZ-794B
(S)-3-[2,6-cis-di(1-naphthylethyl)piperidin-1-yl]propane-1,2-diol
GZ-795A
(R)-3-[2,6-cis-di(2,4-dichlorophenethyl)piperidin-1-yl]propane-1,2-diol
GZ-795B
(S)-3-[2,6-cis-di(2,4-dichlorophenethyl)piperidin-1-yl]propane-1,2-diol
GZ-796A
(R)-3-[2,6-cis-di(4-biphenylethyl)piperidin-1-yl]propane-1,2-diol
GZ-796B
(S)-3-[2,6-cis-di(4-biphenylethyl)piperidin-1-yl]propane-1,2-diol
GZ-797A
(R)-3-[2,6-cis-di(3,4-methylenedioxyphenethyl)piperidin-1-yl]propane-1,2-diol
GZ-797B
(S)-3-[2,6-cis-di(3,4-methylenedioxyphenethyl)piperidin-1-yl]propane-1,2-diol
HPLC
high-performance liquid chromatography
N-1,2-diol
N-1,2-dihydroxypropyl
Ro-4-1284
(2R,3S,11bS)-2-ethyl-3-isobutyl-9,10-dimethoxy-2,2,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol
SAR
structure-activity relationship
SERT
serotonin transporter
UKCP-110
cis-2,5-di-(2-phenethyl)-pyrrolidine hydrochloride
UKMH-106
(3Z,5Z)-3,5-bis(2,4-dichlorobenzylidene)-1-methylpiperidine
VMAT2
vesicular monoamine transporter 2.