TY - JOUR
T1 - GZ-793A inhibits the neurochemical effects of methamphetamine via a selective interaction with the vesicular monoamine transporter-2
AU - Nickell, Justin R.
AU - Siripurapu, Kiran B.
AU - Horton, David B.
AU - Zheng, Guangrong
AU - Crooks, Peter A.
AU - Dwoskin, Linda P.
N1 - Publisher Copyright:
© 2016
PY - 2017
Y1 - 2017
N2 - Lobeline and lobelane inhibit the behavioral and neurochemical effects of methamphetamine via an interaction with the vesicular monoamine transporter-2 (VMAT2). However, lobeline has high affinity for nicotinic receptors, and tolerance develops to the behavioral effects of lobelane. A water-soluble analog of lobelane, R-N-(1,2–dihydroxypropyl)−2,6-cis-di-(4-methoxyphenethyl)piperidine hydrochloride (GZ-793A), also interacts selectively with VMAT2 to inhibit the effects of methamphetamine, but does not produce behavioral tolerance. The current study further evaluated the mechanism underlying the GZ-793A-mediated inhibition of the neurochemical effects of methamphetamine. In contrast to lobeline, GZ-793A does not interact with the agonist recognition site on α4β2*and α7*nicotinic receptors. GZ-793A (0.3–100 µM) inhibited methamphetamine (5 µM)-evoked fractional dopamine release from rat striatal slices, and did not evoke dopamine release in the absence of methamphetamine. Furthermore, GZ-793A (1–100 µM) inhibited neither nicotine (30 µM)-evoked nor electrical field-stimulation-evoked (100 Hz/1 min) fractional dopamine release. Unfortunately, GZ-793A inhibited [3H]dofetilide binding to human-ether-a-go-go related gene channels expressed on human embryonic kidney cells, and further, prolonged action potentials in rabbit cardiac Purkinje fibers, suggesting the potential for GZ-793A to induce ventricular arrhythmias. Thus, GZ-793A selectively inhibits the neurochemical effects of methamphetamine and lacks nicotinic receptor interactions; however, development as a pharmacotherapy for methamphetamine use disorders will not be pursued due to its potential cardiac liabilities.
AB - Lobeline and lobelane inhibit the behavioral and neurochemical effects of methamphetamine via an interaction with the vesicular monoamine transporter-2 (VMAT2). However, lobeline has high affinity for nicotinic receptors, and tolerance develops to the behavioral effects of lobelane. A water-soluble analog of lobelane, R-N-(1,2–dihydroxypropyl)−2,6-cis-di-(4-methoxyphenethyl)piperidine hydrochloride (GZ-793A), also interacts selectively with VMAT2 to inhibit the effects of methamphetamine, but does not produce behavioral tolerance. The current study further evaluated the mechanism underlying the GZ-793A-mediated inhibition of the neurochemical effects of methamphetamine. In contrast to lobeline, GZ-793A does not interact with the agonist recognition site on α4β2*and α7*nicotinic receptors. GZ-793A (0.3–100 µM) inhibited methamphetamine (5 µM)-evoked fractional dopamine release from rat striatal slices, and did not evoke dopamine release in the absence of methamphetamine. Furthermore, GZ-793A (1–100 µM) inhibited neither nicotine (30 µM)-evoked nor electrical field-stimulation-evoked (100 Hz/1 min) fractional dopamine release. Unfortunately, GZ-793A inhibited [3H]dofetilide binding to human-ether-a-go-go related gene channels expressed on human embryonic kidney cells, and further, prolonged action potentials in rabbit cardiac Purkinje fibers, suggesting the potential for GZ-793A to induce ventricular arrhythmias. Thus, GZ-793A selectively inhibits the neurochemical effects of methamphetamine and lacks nicotinic receptor interactions; however, development as a pharmacotherapy for methamphetamine use disorders will not be pursued due to its potential cardiac liabilities.
KW - Dopamine
KW - Drug discovery
KW - Lobelane
KW - Lobeline
KW - Methamphetamine
KW - Vesicular monoamine transporter
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U2 - 10.1016/j.ejphar.2016.12.016
DO - 10.1016/j.ejphar.2016.12.016
M3 - Article
C2 - 27986625
AN - SCOPUS:85008873267
SN - 0014-2999
VL - 795
SP - 143
EP - 149
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
ER -