The Experts below are selected from a list of 318 Experts worldwide ranked by ideXlab platform
Linda P Dwoskin - One of the best experts on this subject based on the ideXlab platform.
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New Scaffold for Lead Compounds to Treat Methamphetamine Use Disorders
The AAPS Journal, 2018Co-Authors: Guangrong Zheng, Peter A Crooks, Michael T. Bardo, Linda P DwoskinAbstract:Despite increased methamphetamine use worldwide, pharmacotherapies are not available to treat methamphetamine use disorder. The vesicular monoamine transporter-2 (VMAT2) is an important pharmacological target for discovery of treatments for methamphetamine use disorder. VMAT2 inhibition by the natural product, Lobeline, reduced methamphetamine-evoked dopamine release, methamphetamine-induced hyperlocomotion, and methamphetamine self-administration in rats. Compared to Lobeline, lobelane exhibited improved affinity and selectivity for VMAT2 over nicotinic acetylcholine receptors. Lobelane inhibited neurochemical and behavioral effects of methamphetamine, but tolerance developed to its behavioral efficacy in reducing methamphetamine self-administration, preventing further development. The lobelane analog, R - N -(1,2-dihydroxypropyl)-2,6- cis -di-(4-methoxyphenethyl)piperidine hydrochloride (GZ-793A), potently and selectively inhibited VMAT2 function and reduced neurochemical and behavioral effects of methamphetamine. However, GZ-793A exhibited potential to induce ventricular arrhythmias interacting with human-ether-a-go-go (hERG) channels. Herein, a new lead, R -3-(4-methoxyphenyl)- N -(1-phenylpropan-2-yl)propan-1-amine (GZ-11610), from the novel scaffold (N-alkyl(1-methyl-2-phenylethyl)amine) was evaluated as a VMAT2 inhibitor and potential therapeutic for methamphetamine use disorder. GZ-11610 was 290-fold selective for VMAT2 over dopamine transporters, suggesting that it may lack abuse liability. GZ-11610 was 640- to 3500-fold selective for VMAT2 over serotonin transporters and nicotinic acetylcholine receptors. GZ-11610 exhibited > 1000-fold selectivity for VMAT2 over hERG, representing a robust improvement relative to our previous VMAT2 inhibitors. GZ-11610 (3–30 mg/kg, s.c. or 56-300 mg/kg, oral) reduced methamphetamine-induced hyperactivity in methamphetamine-sensitized rats. Thus, GZ-11610 is a potent and selective inhibitor of VMAT2, may have low abuse liability and low cardiotoxicity, and after oral administration is effective and specific in inhibiting the locomotor stimulant effects of methamphetamine, suggesting further investigation as a potential therapeutic for methamphetamine use disorder.
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New Scaffold for Lead Compounds to Treat Methamphetamine Use Disorders
The AAPS Journal, 2018Co-Authors: Na-ra Lee, Peter A Crooks, Guangrong Zheng, Michael T. Bardo, Linda P DwoskinAbstract:Despite increased methamphetamine use worldwide, pharmacotherapies are not available to treat methamphetamine use disorder. The vesicular monoamine transporter-2 (VMAT2) is an important pharmacological target for discovery of treatments for methamphetamine use disorder. VMAT2 inhibition by the natural product, Lobeline, reduced methamphetamine-evoked dopamine release, methamphetamine-induced hyperlocomotion, and methamphetamine self-administration in rats. Compared to Lobeline, lobelane exhibited improved affinity and selectivity for VMAT2 over nicotinic acetylcholine receptors. Lobelane inhibited neurochemical and behavioral effects of methamphetamine, but tolerance developed to its behavioral efficacy in reducing methamphetamine self-administration, preventing further development. The lobelane analog, R - N -(1,2-dihydroxypropyl)-2,6- cis -di-(4-methoxyphenethyl)piperidine hydrochloride (GZ-793A), potently and selectively inhibited VMAT2 function and reduced neurochemical and behavioral effects of methamphetamine. However, GZ-793A exhibited potential to induce ventricular arrhythmias interacting with human-ether-a-go-go (hERG) channels. Herein, a new lead, R -3-(4-methoxyphenyl)- N -(1-phenylpropan-2-yl)propan-1-amine (GZ-11610), from the novel scaffold (N-alkyl(1-methyl-2-phenylethyl)amine) was evaluated as a VMAT2 inhibitor and potential therapeutic for methamphetamine use disorder. GZ-11610 was 290-fold selective for VMAT2 over dopamine transporters, suggesting that it may lack abuse liability. GZ-11610 was 640- to 3500-fold selective for VMAT2 over serotonin transporters and nicotinic acetylcholine receptors. GZ-11610 exhibited > 1000-fold selectivity for VMAT2 over hERG, representing a robust improvement relative to our previous VMAT2 inhibitors. GZ-11610 (3–30 mg/kg, s.c. or 56-300 mg/kg, oral) reduced methamphetamine-induced hyperactivity in methamphetamine-sensitized rats. Thus, GZ-11610 is a potent and selective inhibitor of VMAT2, may have low abuse liability and low cardiotoxicity, and after oral administration is effective and specific in inhibiting the locomotor stimulant effects of methamphetamine, suggesting further investigation as a potential therapeutic for methamphetamine use disorder.
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Lobeline attenuates neonatal ethanol-mediated changes in hyperactivity and dopamine transporter function in the prefrontal cortex in rats.
Neuroscience, 2011Co-Authors: A.m. Smith, Kristen Wellmann, T.m. Lundblad, M.l. Carter, Susan Barron, Linda P DwoskinAbstract:Abstract Current therapies for attention deficit hyperactivity disorder (ADHD) have varying efficacy in individuals with fetal alcohol spectrum disorders (FASD), suggesting that alternative therapeutics are needed. Developmental exposure to ethanol produces changes in dopamine (DA) systems, and DA has also been implicated in ADHD pathology. In the current study, Lobeline, which interacts with proteins in dopaminergic presynaptic terminals, was evaluated for its ability to attenuate neonatal ethanol-induced locomotor hyperactivity and alterations in dopamine transporter (DAT) function in striatum and prefrontal cortex (PFC). From postnatal days (PND) 1–7, male and female rat pups were intubated twice daily with either 3 g/kg ethanol or milk, or were not intubated (non-intubated control) as a model for “third trimester” ethanol exposure. On PND 21 and 22, pups received acute Lobeline (0, 0.3, 1, or 3 mg/kg), and locomotor activity was assessed. On PND 23–25, pups again received an acute injection of Lobeline (1 or 3 mg/kg), and DAT kinetic parameters ( Km and V max ) were determined. Results demonstrated that neonatal ethanol produced locomotor hyperactivity on PND 21 that was reversed by Lobeline (1 and 3 mg/kg). Although striatal DAT function was not altered by neonatal ethanol or acute Lobeline, neonatal ethanol exposure increased the V max for DAT in the PFC, suggesting an increase in DAT function in PFC. Lobeline ameliorated this effect on PFC V max at the same doses that decreased hyperactivity. Methylphenidate, the gold standard therapeutic for ADHD, was also evaluated for comparison with Lobeline. Methylphenidate decreased DAT V max and Km in PFC from ethanol-treated pups. Thus, Lobeline and methylphenidate differentially altered DAT function following neonatal ethanol exposure. Collectively, these findings provide support that Lobeline may be a useful pharmacotherapy for some of the deficits associated with neonatal ethanol exposure.
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design synthesis and interaction at the vesicular monoamine transporter 2 of Lobeline analogs potential pharmacotherapies for the treatment of psychostimulant abuse
Current Topics in Medicinal Chemistry, 2011Co-Authors: Peter A Crooks, Guangrong Zheng, David B. Horton, Ashish P Vartak, John P Culver, Fang Zheng, Linda P DwoskinAbstract:The vesicular monoamine transporter-2 (VMAT2) is considered as a new target for the development of novel therapeutics to treat psychostimulant abuse. Current information on the structure, function and role of VMAT2 in psychostimulant abuse are presented. Lobeline, the major alkaloidal constituent of Lobelia inflata, interacts with nicotinic receptors and with VMAT2. Numerous studies have shown that Lobeline inhibits both the neurochemical and behavioral effects of amphetamine in rodents, and behavioral studies demonstrate that Lobeline has potential as a pharmacotherapy for psychostimulant abuse. Systematic structural modification of the Lobeline molecule is described with the aim of improving selectivity and affinity for VMAT2 over neuronal nicotinic acetylcholine receptors and other neurotransmitter transporters. This has led to the discovery of more potent and selective ligands for VMAT2. In addition, a computational neural network analysis of the affinity of these Lobeline analogs for VMAT2 has been carried out, which provides computational models that have predictive value in the rational design of VMAT2 ligands and is also useful in identifying drug candidates from virtual libraries for subsequent synthesis and evaluation.
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lobelane inhibits methamphetamine evoked dopamine release via inhibition of the vesicular monoamine transporter 2
Journal of Pharmacology and Experimental Therapeutics, 2010Co-Authors: Justin R Nickell, Peter A Crooks, Guangrong Zheng, Sairam Krishnamurthy, Seth D Norrholm, Gabriela Deaciuc, Kiran B Siripurapu, Linda P DwoskinAbstract:Lobeline is currently being evaluated in clinical trials as a methamphetamine abuse treatment. Lobeline interacts with nicotinic receptor subtypes, dopamine transporters (DATs), and vesicular monoamine transporters (VMAT2s). Methamphetamine inhibits VMAT2 and promotes dopamine (DA) release from synaptic vesicles, resulting ultimately in increased extracellular DA. The present study generated structure-activity relationships by defunctionalizing the Lobeline molecule and determining effects on [3H]dihydrotetrabenazine binding, inhibition of [3H]DA uptake into striatal synaptic vesicles and synaptosomes, the mechanism of VMAT2 inhibition, and inhibition of methamphetamine-evoked DA release. Compared with Lobeline, the analogs exhibited greater potency inhibiting DA transporter (DAT) function. Saturated analogs, lobelane and nor-lobelane, exhibited high potency (Ki = 45 nM) inhibiting vesicular [3H]DA uptake, and lobelane competitively inhibited VMAT2 function. Lobeline and lobelane exhibited 67- and 35-fold greater potency, respectively, in inhibiting VMAT2 function compared to DAT function. Lobelane potently decreased (IC50 = 0.65 μM; Imax = 73%) methamphetamine-evoked DA overflow, and with a greater maximal effect compared with Lobeline (IC50 = 0.42 μM, Imax = 56.1%). These results provide support for VMAT2 as a target for inhibition of methamphetamine effects. Both trans-isomers and demethylated analogs of lobelane had reduced or unaltered potency inhibiting VMAT2 function and lower maximal inhibition of methamphetamine-evoked DA release compared with lobelane. Thus, defunctionalization, cis-stereochemistry of the side chains, and presence of the piperidino N-methyl are structural features that afford greatest inhibition of methamphetamine-evoked DA release and enhancement of selectivity for VMAT2. The current results reveal that lobelane, a selective VMAT2 inhibitor, inhibits methamphetamine-evoked DA release and is a promising lead for the development of a pharmacotherapeutic for methamphetamine abuse.
Peter A Crooks - One of the best experts on this subject based on the ideXlab platform.
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New Scaffold for Lead Compounds to Treat Methamphetamine Use Disorders
The AAPS Journal, 2018Co-Authors: Na-ra Lee, Peter A Crooks, Guangrong Zheng, Michael T. Bardo, Linda P DwoskinAbstract:Despite increased methamphetamine use worldwide, pharmacotherapies are not available to treat methamphetamine use disorder. The vesicular monoamine transporter-2 (VMAT2) is an important pharmacological target for discovery of treatments for methamphetamine use disorder. VMAT2 inhibition by the natural product, Lobeline, reduced methamphetamine-evoked dopamine release, methamphetamine-induced hyperlocomotion, and methamphetamine self-administration in rats. Compared to Lobeline, lobelane exhibited improved affinity and selectivity for VMAT2 over nicotinic acetylcholine receptors. Lobelane inhibited neurochemical and behavioral effects of methamphetamine, but tolerance developed to its behavioral efficacy in reducing methamphetamine self-administration, preventing further development. The lobelane analog, R - N -(1,2-dihydroxypropyl)-2,6- cis -di-(4-methoxyphenethyl)piperidine hydrochloride (GZ-793A), potently and selectively inhibited VMAT2 function and reduced neurochemical and behavioral effects of methamphetamine. However, GZ-793A exhibited potential to induce ventricular arrhythmias interacting with human-ether-a-go-go (hERG) channels. Herein, a new lead, R -3-(4-methoxyphenyl)- N -(1-phenylpropan-2-yl)propan-1-amine (GZ-11610), from the novel scaffold (N-alkyl(1-methyl-2-phenylethyl)amine) was evaluated as a VMAT2 inhibitor and potential therapeutic for methamphetamine use disorder. GZ-11610 was 290-fold selective for VMAT2 over dopamine transporters, suggesting that it may lack abuse liability. GZ-11610 was 640- to 3500-fold selective for VMAT2 over serotonin transporters and nicotinic acetylcholine receptors. GZ-11610 exhibited > 1000-fold selectivity for VMAT2 over hERG, representing a robust improvement relative to our previous VMAT2 inhibitors. GZ-11610 (3–30 mg/kg, s.c. or 56-300 mg/kg, oral) reduced methamphetamine-induced hyperactivity in methamphetamine-sensitized rats. Thus, GZ-11610 is a potent and selective inhibitor of VMAT2, may have low abuse liability and low cardiotoxicity, and after oral administration is effective and specific in inhibiting the locomotor stimulant effects of methamphetamine, suggesting further investigation as a potential therapeutic for methamphetamine use disorder.
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New Scaffold for Lead Compounds to Treat Methamphetamine Use Disorders
The AAPS Journal, 2018Co-Authors: Guangrong Zheng, Peter A Crooks, Michael T. Bardo, Linda P DwoskinAbstract:Despite increased methamphetamine use worldwide, pharmacotherapies are not available to treat methamphetamine use disorder. The vesicular monoamine transporter-2 (VMAT2) is an important pharmacological target for discovery of treatments for methamphetamine use disorder. VMAT2 inhibition by the natural product, Lobeline, reduced methamphetamine-evoked dopamine release, methamphetamine-induced hyperlocomotion, and methamphetamine self-administration in rats. Compared to Lobeline, lobelane exhibited improved affinity and selectivity for VMAT2 over nicotinic acetylcholine receptors. Lobelane inhibited neurochemical and behavioral effects of methamphetamine, but tolerance developed to its behavioral efficacy in reducing methamphetamine self-administration, preventing further development. The lobelane analog, R - N -(1,2-dihydroxypropyl)-2,6- cis -di-(4-methoxyphenethyl)piperidine hydrochloride (GZ-793A), potently and selectively inhibited VMAT2 function and reduced neurochemical and behavioral effects of methamphetamine. However, GZ-793A exhibited potential to induce ventricular arrhythmias interacting with human-ether-a-go-go (hERG) channels. Herein, a new lead, R -3-(4-methoxyphenyl)- N -(1-phenylpropan-2-yl)propan-1-amine (GZ-11610), from the novel scaffold (N-alkyl(1-methyl-2-phenylethyl)amine) was evaluated as a VMAT2 inhibitor and potential therapeutic for methamphetamine use disorder. GZ-11610 was 290-fold selective for VMAT2 over dopamine transporters, suggesting that it may lack abuse liability. GZ-11610 was 640- to 3500-fold selective for VMAT2 over serotonin transporters and nicotinic acetylcholine receptors. GZ-11610 exhibited > 1000-fold selectivity for VMAT2 over hERG, representing a robust improvement relative to our previous VMAT2 inhibitors. GZ-11610 (3–30 mg/kg, s.c. or 56-300 mg/kg, oral) reduced methamphetamine-induced hyperactivity in methamphetamine-sensitized rats. Thus, GZ-11610 is a potent and selective inhibitor of VMAT2, may have low abuse liability and low cardiotoxicity, and after oral administration is effective and specific in inhibiting the locomotor stimulant effects of methamphetamine, suggesting further investigation as a potential therapeutic for methamphetamine use disorder.
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Synthesis of Lobeline, Lobelane and their Analogues. A Review
Organic preparations and procedures international, 2015Co-Authors: Guangrong Zheng, Peter A CrooksAbstract:(-)-Lobeline (1) (2R, 6S, 10S-, Fig. 1) is the major alkaloidal constituent of Lobelia inflata, a plant native to North America with a long history of use as a natural remedy. The plant is also cal...
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design synthesis and interaction at the vesicular monoamine transporter 2 of Lobeline analogs potential pharmacotherapies for the treatment of psychostimulant abuse
Current Topics in Medicinal Chemistry, 2011Co-Authors: Peter A Crooks, Guangrong Zheng, David B. Horton, Ashish P Vartak, John P Culver, Fang Zheng, Linda P DwoskinAbstract:The vesicular monoamine transporter-2 (VMAT2) is considered as a new target for the development of novel therapeutics to treat psychostimulant abuse. Current information on the structure, function and role of VMAT2 in psychostimulant abuse are presented. Lobeline, the major alkaloidal constituent of Lobelia inflata, interacts with nicotinic receptors and with VMAT2. Numerous studies have shown that Lobeline inhibits both the neurochemical and behavioral effects of amphetamine in rodents, and behavioral studies demonstrate that Lobeline has potential as a pharmacotherapy for psychostimulant abuse. Systematic structural modification of the Lobeline molecule is described with the aim of improving selectivity and affinity for VMAT2 over neuronal nicotinic acetylcholine receptors and other neurotransmitter transporters. This has led to the discovery of more potent and selective ligands for VMAT2. In addition, a computational neural network analysis of the affinity of these Lobeline analogs for VMAT2 has been carried out, which provides computational models that have predictive value in the rational design of VMAT2 ligands and is also useful in identifying drug candidates from virtual libraries for subsequent synthesis and evaluation.
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lobelane inhibits methamphetamine evoked dopamine release via inhibition of the vesicular monoamine transporter 2
Journal of Pharmacology and Experimental Therapeutics, 2010Co-Authors: Justin R Nickell, Peter A Crooks, Guangrong Zheng, Sairam Krishnamurthy, Seth D Norrholm, Gabriela Deaciuc, Kiran B Siripurapu, Linda P DwoskinAbstract:Lobeline is currently being evaluated in clinical trials as a methamphetamine abuse treatment. Lobeline interacts with nicotinic receptor subtypes, dopamine transporters (DATs), and vesicular monoamine transporters (VMAT2s). Methamphetamine inhibits VMAT2 and promotes dopamine (DA) release from synaptic vesicles, resulting ultimately in increased extracellular DA. The present study generated structure-activity relationships by defunctionalizing the Lobeline molecule and determining effects on [3H]dihydrotetrabenazine binding, inhibition of [3H]DA uptake into striatal synaptic vesicles and synaptosomes, the mechanism of VMAT2 inhibition, and inhibition of methamphetamine-evoked DA release. Compared with Lobeline, the analogs exhibited greater potency inhibiting DA transporter (DAT) function. Saturated analogs, lobelane and nor-lobelane, exhibited high potency (Ki = 45 nM) inhibiting vesicular [3H]DA uptake, and lobelane competitively inhibited VMAT2 function. Lobeline and lobelane exhibited 67- and 35-fold greater potency, respectively, in inhibiting VMAT2 function compared to DAT function. Lobelane potently decreased (IC50 = 0.65 μM; Imax = 73%) methamphetamine-evoked DA overflow, and with a greater maximal effect compared with Lobeline (IC50 = 0.42 μM, Imax = 56.1%). These results provide support for VMAT2 as a target for inhibition of methamphetamine effects. Both trans-isomers and demethylated analogs of lobelane had reduced or unaltered potency inhibiting VMAT2 function and lower maximal inhibition of methamphetamine-evoked DA release compared with lobelane. Thus, defunctionalization, cis-stereochemistry of the side chains, and presence of the piperidino N-methyl are structural features that afford greatest inhibition of methamphetamine-evoked DA release and enhancement of selectivity for VMAT2. The current results reveal that lobelane, a selective VMAT2 inhibitor, inhibits methamphetamine-evoked DA release and is a promising lead for the development of a pharmacotherapeutic for methamphetamine abuse.
Guangrong Zheng - One of the best experts on this subject based on the ideXlab platform.
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New Scaffold for Lead Compounds to Treat Methamphetamine Use Disorders
The AAPS Journal, 2018Co-Authors: Guangrong Zheng, Peter A Crooks, Michael T. Bardo, Linda P DwoskinAbstract:Despite increased methamphetamine use worldwide, pharmacotherapies are not available to treat methamphetamine use disorder. The vesicular monoamine transporter-2 (VMAT2) is an important pharmacological target for discovery of treatments for methamphetamine use disorder. VMAT2 inhibition by the natural product, Lobeline, reduced methamphetamine-evoked dopamine release, methamphetamine-induced hyperlocomotion, and methamphetamine self-administration in rats. Compared to Lobeline, lobelane exhibited improved affinity and selectivity for VMAT2 over nicotinic acetylcholine receptors. Lobelane inhibited neurochemical and behavioral effects of methamphetamine, but tolerance developed to its behavioral efficacy in reducing methamphetamine self-administration, preventing further development. The lobelane analog, R - N -(1,2-dihydroxypropyl)-2,6- cis -di-(4-methoxyphenethyl)piperidine hydrochloride (GZ-793A), potently and selectively inhibited VMAT2 function and reduced neurochemical and behavioral effects of methamphetamine. However, GZ-793A exhibited potential to induce ventricular arrhythmias interacting with human-ether-a-go-go (hERG) channels. Herein, a new lead, R -3-(4-methoxyphenyl)- N -(1-phenylpropan-2-yl)propan-1-amine (GZ-11610), from the novel scaffold (N-alkyl(1-methyl-2-phenylethyl)amine) was evaluated as a VMAT2 inhibitor and potential therapeutic for methamphetamine use disorder. GZ-11610 was 290-fold selective for VMAT2 over dopamine transporters, suggesting that it may lack abuse liability. GZ-11610 was 640- to 3500-fold selective for VMAT2 over serotonin transporters and nicotinic acetylcholine receptors. GZ-11610 exhibited > 1000-fold selectivity for VMAT2 over hERG, representing a robust improvement relative to our previous VMAT2 inhibitors. GZ-11610 (3–30 mg/kg, s.c. or 56-300 mg/kg, oral) reduced methamphetamine-induced hyperactivity in methamphetamine-sensitized rats. Thus, GZ-11610 is a potent and selective inhibitor of VMAT2, may have low abuse liability and low cardiotoxicity, and after oral administration is effective and specific in inhibiting the locomotor stimulant effects of methamphetamine, suggesting further investigation as a potential therapeutic for methamphetamine use disorder.
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New Scaffold for Lead Compounds to Treat Methamphetamine Use Disorders
The AAPS Journal, 2018Co-Authors: Na-ra Lee, Peter A Crooks, Guangrong Zheng, Michael T. Bardo, Linda P DwoskinAbstract:Despite increased methamphetamine use worldwide, pharmacotherapies are not available to treat methamphetamine use disorder. The vesicular monoamine transporter-2 (VMAT2) is an important pharmacological target for discovery of treatments for methamphetamine use disorder. VMAT2 inhibition by the natural product, Lobeline, reduced methamphetamine-evoked dopamine release, methamphetamine-induced hyperlocomotion, and methamphetamine self-administration in rats. Compared to Lobeline, lobelane exhibited improved affinity and selectivity for VMAT2 over nicotinic acetylcholine receptors. Lobelane inhibited neurochemical and behavioral effects of methamphetamine, but tolerance developed to its behavioral efficacy in reducing methamphetamine self-administration, preventing further development. The lobelane analog, R - N -(1,2-dihydroxypropyl)-2,6- cis -di-(4-methoxyphenethyl)piperidine hydrochloride (GZ-793A), potently and selectively inhibited VMAT2 function and reduced neurochemical and behavioral effects of methamphetamine. However, GZ-793A exhibited potential to induce ventricular arrhythmias interacting with human-ether-a-go-go (hERG) channels. Herein, a new lead, R -3-(4-methoxyphenyl)- N -(1-phenylpropan-2-yl)propan-1-amine (GZ-11610), from the novel scaffold (N-alkyl(1-methyl-2-phenylethyl)amine) was evaluated as a VMAT2 inhibitor and potential therapeutic for methamphetamine use disorder. GZ-11610 was 290-fold selective for VMAT2 over dopamine transporters, suggesting that it may lack abuse liability. GZ-11610 was 640- to 3500-fold selective for VMAT2 over serotonin transporters and nicotinic acetylcholine receptors. GZ-11610 exhibited > 1000-fold selectivity for VMAT2 over hERG, representing a robust improvement relative to our previous VMAT2 inhibitors. GZ-11610 (3–30 mg/kg, s.c. or 56-300 mg/kg, oral) reduced methamphetamine-induced hyperactivity in methamphetamine-sensitized rats. Thus, GZ-11610 is a potent and selective inhibitor of VMAT2, may have low abuse liability and low cardiotoxicity, and after oral administration is effective and specific in inhibiting the locomotor stimulant effects of methamphetamine, suggesting further investigation as a potential therapeutic for methamphetamine use disorder.
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Synthesis of Lobeline, Lobelane and their Analogues. A Review
Organic preparations and procedures international, 2015Co-Authors: Guangrong Zheng, Peter A CrooksAbstract:(-)-Lobeline (1) (2R, 6S, 10S-, Fig. 1) is the major alkaloidal constituent of Lobelia inflata, a plant native to North America with a long history of use as a natural remedy. The plant is also cal...
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design synthesis and interaction at the vesicular monoamine transporter 2 of Lobeline analogs potential pharmacotherapies for the treatment of psychostimulant abuse
Current Topics in Medicinal Chemistry, 2011Co-Authors: Peter A Crooks, Guangrong Zheng, David B. Horton, Ashish P Vartak, John P Culver, Fang Zheng, Linda P DwoskinAbstract:The vesicular monoamine transporter-2 (VMAT2) is considered as a new target for the development of novel therapeutics to treat psychostimulant abuse. Current information on the structure, function and role of VMAT2 in psychostimulant abuse are presented. Lobeline, the major alkaloidal constituent of Lobelia inflata, interacts with nicotinic receptors and with VMAT2. Numerous studies have shown that Lobeline inhibits both the neurochemical and behavioral effects of amphetamine in rodents, and behavioral studies demonstrate that Lobeline has potential as a pharmacotherapy for psychostimulant abuse. Systematic structural modification of the Lobeline molecule is described with the aim of improving selectivity and affinity for VMAT2 over neuronal nicotinic acetylcholine receptors and other neurotransmitter transporters. This has led to the discovery of more potent and selective ligands for VMAT2. In addition, a computational neural network analysis of the affinity of these Lobeline analogs for VMAT2 has been carried out, which provides computational models that have predictive value in the rational design of VMAT2 ligands and is also useful in identifying drug candidates from virtual libraries for subsequent synthesis and evaluation.
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lobelane inhibits methamphetamine evoked dopamine release via inhibition of the vesicular monoamine transporter 2
Journal of Pharmacology and Experimental Therapeutics, 2010Co-Authors: Justin R Nickell, Peter A Crooks, Guangrong Zheng, Sairam Krishnamurthy, Seth D Norrholm, Gabriela Deaciuc, Kiran B Siripurapu, Linda P DwoskinAbstract:Lobeline is currently being evaluated in clinical trials as a methamphetamine abuse treatment. Lobeline interacts with nicotinic receptor subtypes, dopamine transporters (DATs), and vesicular monoamine transporters (VMAT2s). Methamphetamine inhibits VMAT2 and promotes dopamine (DA) release from synaptic vesicles, resulting ultimately in increased extracellular DA. The present study generated structure-activity relationships by defunctionalizing the Lobeline molecule and determining effects on [3H]dihydrotetrabenazine binding, inhibition of [3H]DA uptake into striatal synaptic vesicles and synaptosomes, the mechanism of VMAT2 inhibition, and inhibition of methamphetamine-evoked DA release. Compared with Lobeline, the analogs exhibited greater potency inhibiting DA transporter (DAT) function. Saturated analogs, lobelane and nor-lobelane, exhibited high potency (Ki = 45 nM) inhibiting vesicular [3H]DA uptake, and lobelane competitively inhibited VMAT2 function. Lobeline and lobelane exhibited 67- and 35-fold greater potency, respectively, in inhibiting VMAT2 function compared to DAT function. Lobelane potently decreased (IC50 = 0.65 μM; Imax = 73%) methamphetamine-evoked DA overflow, and with a greater maximal effect compared with Lobeline (IC50 = 0.42 μM, Imax = 56.1%). These results provide support for VMAT2 as a target for inhibition of methamphetamine effects. Both trans-isomers and demethylated analogs of lobelane had reduced or unaltered potency inhibiting VMAT2 function and lower maximal inhibition of methamphetamine-evoked DA release compared with lobelane. Thus, defunctionalization, cis-stereochemistry of the side chains, and presence of the piperidino N-methyl are structural features that afford greatest inhibition of methamphetamine-evoked DA release and enhancement of selectivity for VMAT2. The current results reveal that lobelane, a selective VMAT2 inhibitor, inhibits methamphetamine-evoked DA release and is a promising lead for the development of a pharmacotherapeutic for methamphetamine abuse.
Dennis K. Miller - One of the best experts on this subject based on the ideXlab platform.
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Lobeline Attenuates the Locomotor-Activating Properties of Repeated Morphine Treatment in Rats
Tropical Journal of Pharmaceutical Research, 2011Co-Authors: Dennis K. Miller, James E. Polston, Kelli R. Rodvelt, Matthew J. WillAbstract:Purpose: Lobeline perturbs intra- and extracellular neurotransmitter levels and diminishes the in vitro and in vivo effects of psychostimulants. More recently, Lobeline was shown to bind to μ opiate receptors, block the effects of opiate receptor agonists, and decrease heroin self-administration in rats. The present study determined the effect of Lobeline on morphine-induced changes in locomotor behavior in rats. Methods: For 12 consecutive days (Days 1 - 12), male rats were administered Lobeline (0.3 or 1 mg/kg) followed by morphine (5 or 10 mg/kg) and locomotor activity was measured. On Day 13, the effect of Lobeline on the expression of morphine-induced increases in activity was determined. Results: With repeated morphine treatment, an increase in locomotor activity was observed. In a dosedependent manner, Lobeline decreased the morphine-induced increase in activity. Acute Lobeline challenge on Day 13 also attenuated the expression of this morphine-induced increase in activity. Conclusion: These results are consistent with previous work where Lobeline blocks the locomotoractivtating properties of psychostimulants, and these findings support an emerging literature suggesting that Lobeline produces its behavioral effects through an interaction with μ opiate receptors. Keywords: Behavior, Morphine, Locomotor activity, Behavioural sensitization, μ Opiate receptors
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Dose-dependent attenuation of heroin self-administration with Lobeline.
Journal of psychopharmacology (Oxford England), 2010Co-Authors: Nigel Hart, Dennis K. Miller, Angelica Rocha, Jack R. NationAbstract:Behavioural studies have yielded results that show Lobeline has the ability to attenuate d-methamphetamine self-administration. Further in vivo and in vitro studies have demonstrated a blockade of μ-opioid receptors with Lobeline. The present investigation examined the ability of Lobeline to attenuate heroin intravenous (i.v.) self-administration when administered prior to testing. Male Sprague—Dawley rats were surgically implanted with jugular catheters and trained to lever press for i.v. heroin infusions (18 μg/kg) under a fixed ratio-2 schedule wherein two active lever presses resulted in heroin delivery. Rats then were tested for heroin self-administration after pretreatment with subcutaneous Lobeline injections (0.3, 1.0, or 3.0 mg/kg, 15 min prior to testing sessions). At doses of 1.0 and 3.0 mg/kg, Lobeline attenuated self-administration of heroin. The results suggest a potential for Lobeline to be used in pharmacotherapy for opioid abuse.
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Lobeline esters as novel ligands for neuronal nicotinic acetylcholine receptors and neurotransmitter transporters.
Bioorganic & medicinal chemistry, 2009Co-Authors: Marhaba Hojahmat, Linda P Dwoskin, Seth D Norrholm, Agripina G Deaciuc, Dennis K. Miller, Vladimir P. Grinevich, David B. Horton, Peter A CrooksAbstract:Vesicular monoamine transporter-2 (VMAT2) is a viable target for development of pharmacotherapies for psychostimulant abuse. Lobeline (1) is a potent antagonist at alpha4beta2 * nicotinic acetylcholine receptors, has moderate affinity (K(i)=5.46microM) for VMAT2, and is being investigated currently as a clinical candidate for treatment of psychostimulant abuse. A series of carboxylic acid and sulfonic acid ester analogs 2-20 of Lobeline were synthesized and evaluated for interaction with alpha4beta2 * and alpha7 * neuronal nicotinic acetylcholine receptors (nAChRs), the dopamine transporter (DAT), serotonin transporter (SERT) and VMAT2. Both carboxylic acid and sulfonic acid esters had low affinity at alpha7 * nAChRs. Similar to Lobeline (K(i)=4nM), sulfonic acid esters had high affinity at alpha4beta2 * (K(i)=5-17nM). Aromatic carboxylic acid ester analogs of Lobeline (2-4) were 100-1000-fold less potent than Lobeline at alpha4beta2 * nAChRs, whereas aliphatic carboxylic acid ester analogs were 10-100-fold less potent than Lobeline at alpha4beta2 *. Two representative Lobeline esters, the 10-O-benzoate (2) and the 10-O-benzenesulfonate (10) were evaluated in the (36)Rb(+) efflux assay using rat thalamic synaptosomes, and were shown to be antagonists with IC(50) values of 0.85microM and 1.60microM, respectively. Both carboxylic and sulfonic acid esters exhibited a range of potencies (equipotent to 13-45-fold greater potency compared to Lobeline) for inhibiting DAT and SERT, respectively, and like Lobeline, had moderate affinity (K(i)=1.98-10.8microM) for VMAT2. One of the more interesting analogs, p-methoxybenzoic acid ester 4, had low affinity at alpha4beta2 * nAChRs (K(i)=19.3microM) and was equipotent with Lobeline, at VMAT2 (K(i)=2.98microM), exhibiting a 6.5-fold selectivity for VMAT2 over alpha4beta2 nAChRs. Thus, esterification of the Lobeline molecule may be a useful structural modification for the development of Lobeline analogs with improved selectivity at VMAT2.
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Lobeline, a potential pharmacotherapy for drug addiction, binds to μ opioid receptors and diminishes the effects of opioid receptor agonists
Drug and Alcohol Dependence, 2007Co-Authors: Dennis K. Miller, Kelli R. Rodvelt, John R. Lever, James A. Baskett, Matthew J. Will, George R. KrackeAbstract:Abstract Lobeline diminishes the behavioral and neurochemical effects of nicotine and amphetamines, and is considered a potential pharmacotherapy for drug abuse and addiction. Lobeline has high affinity for nicotinic acetylcholine receptors and inhibits the function of vesicular monoamine and dopamine transporters. The present study investigated the less-explored interaction of Lobeline and the endogenous opioid system. In guinea pig brain homogenates, Lobeline displaced ( K i = 0.74 μM) the binding of [ 3 H]DAMGO [(D-Ala 2 , N -ME-Phe 4 , Gly 5 -ol)-enkephalin]. In a functional assay system comprised of MOR-1 μ opioid receptors and GIRK2 potassium channels expressed in Xenopus oocytes, Lobeline had no effect on the resting current, but maximally inhibited (IC 50 = 1.1 μM) morphine- and DAMGO-activated potassium current in a concentration-dependent manner. In a second functional assay, Lobeline-evoked [ 3 H]overflow from rat striatal slices preloaded with [ 3 H]dopamine was not blocked by naltrexone. Importantly, concentrations of Lobeline (0.1–0.3 μM) that did not have intrinsic activity attenuated (∼50%) morphine-evoked [ 3 H]overflow. Overall, the results suggest that Lobeline functions as a μ opioid receptor antagonist. The ability of Lobeline to block psychostimulant effects may be mediated by opioid receptor antagonism, and Lobeline could be investigated as a treatment for opiate addiction.
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Lobeline, a potential pharmacotherapy for drug addiction, binds to mu opioid receptors and diminishes the effects of opioid receptor agonists.
Drug and alcohol dependence, 2007Co-Authors: Dennis K. Miller, Kelli R. Rodvelt, John R. Lever, James A. Baskett, Matthew J. Will, George R. KrackeAbstract:Lobeline diminishes the behavioral and neurochemical effects of nicotine and amphetamines, and is considered a potential pharmacotherapy for drug abuse and addiction. Lobeline has high affinity for nicotinic acetylcholine receptors and inhibits the function of vesicular monoamine and dopamine transporters. The present study investigated the less-explored interaction of Lobeline and the endogenous opioid system. In guinea pig brain homogenates, Lobeline displaced (K(i)=0.74 microM) the binding of [(3)H]DAMGO [(D-Ala(2), N-ME-Phe(4), Gly(5)-ol)-enkephalin]. In a functional assay system comprised of MOR-1 mu opioid receptors and GIRK2 potassium channels expressed in Xenopus oocytes, Lobeline had no effect on the resting current, but maximally inhibited (IC(50)=1.1 microM) morphine- and DAMGO-activated potassium current in a concentration-dependent manner. In a second functional assay, Lobeline-evoked [(3)H]overflow from rat striatal slices preloaded with [(3)H]dopamine was not blocked by naltrexone. Importantly, concentrations of Lobeline (0.1-0.3 microM) that did not have intrinsic activity attenuated ( approximately 50%) morphine-evoked [(3)H]overflow. Overall, the results suggest that Lobeline functions as a mu opioid receptor antagonist. The ability of Lobeline to block psychostimulant effects may be mediated by opioid receptor antagonism, and Lobeline could be investigated as a treatment for opiate addiction.
Michael T. Bardo - One of the best experts on this subject based on the ideXlab platform.
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New Scaffold for Lead Compounds to Treat Methamphetamine Use Disorders
The AAPS Journal, 2018Co-Authors: Guangrong Zheng, Peter A Crooks, Michael T. Bardo, Linda P DwoskinAbstract:Despite increased methamphetamine use worldwide, pharmacotherapies are not available to treat methamphetamine use disorder. The vesicular monoamine transporter-2 (VMAT2) is an important pharmacological target for discovery of treatments for methamphetamine use disorder. VMAT2 inhibition by the natural product, Lobeline, reduced methamphetamine-evoked dopamine release, methamphetamine-induced hyperlocomotion, and methamphetamine self-administration in rats. Compared to Lobeline, lobelane exhibited improved affinity and selectivity for VMAT2 over nicotinic acetylcholine receptors. Lobelane inhibited neurochemical and behavioral effects of methamphetamine, but tolerance developed to its behavioral efficacy in reducing methamphetamine self-administration, preventing further development. The lobelane analog, R - N -(1,2-dihydroxypropyl)-2,6- cis -di-(4-methoxyphenethyl)piperidine hydrochloride (GZ-793A), potently and selectively inhibited VMAT2 function and reduced neurochemical and behavioral effects of methamphetamine. However, GZ-793A exhibited potential to induce ventricular arrhythmias interacting with human-ether-a-go-go (hERG) channels. Herein, a new lead, R -3-(4-methoxyphenyl)- N -(1-phenylpropan-2-yl)propan-1-amine (GZ-11610), from the novel scaffold (N-alkyl(1-methyl-2-phenylethyl)amine) was evaluated as a VMAT2 inhibitor and potential therapeutic for methamphetamine use disorder. GZ-11610 was 290-fold selective for VMAT2 over dopamine transporters, suggesting that it may lack abuse liability. GZ-11610 was 640- to 3500-fold selective for VMAT2 over serotonin transporters and nicotinic acetylcholine receptors. GZ-11610 exhibited > 1000-fold selectivity for VMAT2 over hERG, representing a robust improvement relative to our previous VMAT2 inhibitors. GZ-11610 (3–30 mg/kg, s.c. or 56-300 mg/kg, oral) reduced methamphetamine-induced hyperactivity in methamphetamine-sensitized rats. Thus, GZ-11610 is a potent and selective inhibitor of VMAT2, may have low abuse liability and low cardiotoxicity, and after oral administration is effective and specific in inhibiting the locomotor stimulant effects of methamphetamine, suggesting further investigation as a potential therapeutic for methamphetamine use disorder.
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New Scaffold for Lead Compounds to Treat Methamphetamine Use Disorders
The AAPS Journal, 2018Co-Authors: Na-ra Lee, Peter A Crooks, Guangrong Zheng, Michael T. Bardo, Linda P DwoskinAbstract:Despite increased methamphetamine use worldwide, pharmacotherapies are not available to treat methamphetamine use disorder. The vesicular monoamine transporter-2 (VMAT2) is an important pharmacological target for discovery of treatments for methamphetamine use disorder. VMAT2 inhibition by the natural product, Lobeline, reduced methamphetamine-evoked dopamine release, methamphetamine-induced hyperlocomotion, and methamphetamine self-administration in rats. Compared to Lobeline, lobelane exhibited improved affinity and selectivity for VMAT2 over nicotinic acetylcholine receptors. Lobelane inhibited neurochemical and behavioral effects of methamphetamine, but tolerance developed to its behavioral efficacy in reducing methamphetamine self-administration, preventing further development. The lobelane analog, R - N -(1,2-dihydroxypropyl)-2,6- cis -di-(4-methoxyphenethyl)piperidine hydrochloride (GZ-793A), potently and selectively inhibited VMAT2 function and reduced neurochemical and behavioral effects of methamphetamine. However, GZ-793A exhibited potential to induce ventricular arrhythmias interacting with human-ether-a-go-go (hERG) channels. Herein, a new lead, R -3-(4-methoxyphenyl)- N -(1-phenylpropan-2-yl)propan-1-amine (GZ-11610), from the novel scaffold (N-alkyl(1-methyl-2-phenylethyl)amine) was evaluated as a VMAT2 inhibitor and potential therapeutic for methamphetamine use disorder. GZ-11610 was 290-fold selective for VMAT2 over dopamine transporters, suggesting that it may lack abuse liability. GZ-11610 was 640- to 3500-fold selective for VMAT2 over serotonin transporters and nicotinic acetylcholine receptors. GZ-11610 exhibited > 1000-fold selectivity for VMAT2 over hERG, representing a robust improvement relative to our previous VMAT2 inhibitors. GZ-11610 (3–30 mg/kg, s.c. or 56-300 mg/kg, oral) reduced methamphetamine-induced hyperactivity in methamphetamine-sensitized rats. Thus, GZ-11610 is a potent and selective inhibitor of VMAT2, may have low abuse liability and low cardiotoxicity, and after oral administration is effective and specific in inhibiting the locomotor stimulant effects of methamphetamine, suggesting further investigation as a potential therapeutic for methamphetamine use disorder.
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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
2010Co-Authors: Methamphetamine Self-administration In Rats□s, Peter A Crooks, Linda P Dwoskin, Justin R Nickell, Kiran B Siripurapu, Joshua S. Beckmann, David B. Horton, Emily D. Denehy, Ashish Vartak, Michael T. BardoAbstract:Both Lobeline and lobelane attenuate methamphetamine self-administration in rats by decreasing methamphetamine-induced dopamine release via interaction with vesicular monoamine trans-porter-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 hydro-chloride (UKCP-112), were evaluated for inhibition of [3H]dihy-drotetrabenazine binding and [3H]dopamine uptake by using a rat synaptic vesicle preparation to assess VMAT2 interaction. Com-pounds were evaluated for inhibition of [3H]nicotine and [3H]me-thyllycaconitine binding to assess interaction with the major nic-otinic receptor subtypes. In addition, compounds were evaluated for inhibition of methamphetamine-evoked endogenous dopa-mine release by using striatal slices. The most promising com-pound, 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 in-hibited [3H]dihydrotetrabenazine binding (Ki 2.66 0.37, 1.05 0.10, and 3.80 0.31 M, respectively) and had high potenc
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Lobelane decreases methamphetamine self-administration in rats
European journal of pharmacology, 2007Co-Authors: Nichole M. Neugebauer, Peter A Crooks, Linda P Dwoskin, Steven B. Harrod, Dustin J. Stairs, Michael T. BardoAbstract:Lobelane, a minor alkaloid of Lobelia inflata and a synthetic, des-oxy analog of Lobeline, has good affinity for the vesicular monoamine transporter and the dopamine transporter. The current study examined the ability of lobelane to specifically decrease methamphetamine self-administration. Rats were trained on a fixed ratio 5 schedule of reinforcement to self-administer methamphetamine (0.05 mg/kg/infusion, i.v.) or to respond for sucrose pellets. Upon reaching stable responding, rats were pretreated with lobelane (0.1, 1, 3, 5.6, or 10 mg/kg, s.c.) or saline, 15 min prior to the operant session. To assess the effect of repeated lobelane on methamphetamine self-administration, rats were pretreated with lobelane (5.6 or 10 mg/kg, s.c.) for 7 sessions. Behavioral specificity was further investigated by assessing the effects of lobelane (0.1, 1, 3, 5, or 10 mg/kg, s.c.) or saline on locomotor activity. Within the dose range tested, lobelane dose-dependently decreased methamphetamine self-administration, while having no effect on sucrose-maintained responding. Locomotor activity was decreased following only the highest dose of lobelane (10 mg/kg). Across repeated pretreatments, tolerance developed to the effect of lobelane on methamphetamine self-administration, demonstrating that the ability of lobelane to specifically decrease methamphetamine self-administration is a transient effect. Thus, taken together, the results show that although lobelane interacts with the pharmacological targets believed to be responsible for its ability to decrease methamphetamine self-administration, removal of the oxygen functionalities from the Lobeline molecule may have afforded a compound with an altered pharmacokinetic and/or pharmacodynamic profile.
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Lobeline produces conditioned taste avoidance in rats.
Pharmacology biochemistry and behavior, 2004Co-Authors: Steven B. Harrod, Linda P Dwoskin, Michael T. BardoAbstract:Previous results indicate that pretreatment with Lobeline attenuates methamphetamine (METH) self-administration in rats, but not by acting as a substitute reinforcer. Given these findings, it has been suggested that Lobeline may serve as a useful pharmacotherapy for psychostimulant abuse. However, because Lobeline produces emesis and nausea in humans, the present study examined whether Lobeline has direct effects on taste avoidance behavior in rats within the same dose range shown previously to decrease METH self-administration. Two experiments utilized a Pavlovian conditioning procedure to determine if Lobeline produces conditioned taste avoidance (CTA) in rats. In Experiments 1 and 2, rats consumed either novel milk or salt solutions, respectively, and within 10 min, were injected with Lobeline (0.3-3.0 mg/kg) or METH (0.3-3.0 mg/kg). A single-bottle test conducted 48 h after flavor-drug pairings indicated that the dose of Lobeline that reduced METH self-administration in a previous study (i.e., 3.0 mg/kg) also produced reliable CTA for milk and salt solution. These findings suggest a need to develop Lobeline analogs that reduce METH self-administration, but do not produce CTA following the consumption of a novel solution.