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Research ArticleNEUROPHARMACOLOGY

Lobeline Analogs with Enhanced Affinity and Selectivity for Plasmalemma and Vesicular Monoamine Transporters

Dennis K. Miller, Peter A. Crooks, Guangrong Zheng, Vladimir P. Grinevich, Seth D. Norrholm and Linda P. Dwoskin
Journal of Pharmacology and Experimental Therapeutics September 2004, 310 (3) 1035-1045; DOI: https://doi.org/10.1124/jpet.104.068098
Dennis K. Miller
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Peter A. Crooks
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Guangrong Zheng
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Vladimir P. Grinevich
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Seth D. Norrholm
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Linda P. Dwoskin
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Abstract

Lobeline attenuates the behavioral effects of psychostimulants in rodents and inhibits the function of nicotinic receptors (nAChRs), dopamine transporters (DATs), and vesicular monoamine transporters (VMAT2s). Monoamine transporters are considered valid targets for drug development for the treatment of methamphetamine abuse. In the current study, a series of lobeline analogs were evaluated for affinity and selectivity at these targets. None of the analogs was more potent than nicotine at the [3H]methyllycaconitine binding site (α7* nAChR subtype). Lobeline tosylate was equipotent with lobeline in inhibiting [3H]nicotine binding but 70-fold more potent in inhibiting nicotine-evoked 86Rb+ efflux, demonstrating antagonism of α4β2* nAChRs. Compared with lobeline, the defunctionalized analogs lobelane, mesotransdiene, and (-)-trans-transdiene showed dramatically reduced affinity at α4β2* nAChRs and a 15- to 100-fold higher affinity (Ki = 1.95, 0.58, and 0.26 μM, respectively) at DATs. Mesotransdiene and (-)-trans-transdiene competitively inhibited DAT function, whereas lobelane and lobeline acted noncompetitively. 10S/10R-MEPP [N-methyl-2R-(2R/2S-hydroxy-2-phenylethyl)6S-(2-phenylethyl)piperidine] and 10R-MESP [N-methyl-2R-(2R-hydroxy-2-phenylethyl)6S-(2-phenylethen-1-yl)piperidine] were 2 to 3 orders of magnitude more potent (Ki = 0.01 and 0.04 μM, respectively) than lobeline in inhibiting [3H]serotonin uptake; 10S/10R-MEPP showed a 600-fold selectivity for this transporter. Uptake results using hDATs and human serotonin transporters expressed in human embryonic kidney-293 cells were consistent with native transporter assays. Lobelane and ketoalkene were 5-fold more potent (Ki = 0.92 and 1.35 μM, respectively) than lobeline (Ki = 5.46 μM) in inhibiting [3H]methoxytetrabenazine binding to VMAT2 in vesicle preparations. Thus, structural modification (defunctionalization) of the lobeline molecule markedly decreases affinity for α4β2* and α7* nAChRs while increasing affinity for neurotransmitter transporters, affording analogs with enhanced selectivity for these transporters and providing new leads for the treatment of psychostimulant abuse.

Footnotes

  • This research was supported by NIH Grants DA 06043, DA 07304, DA 00399, and DA 13519. National Institute on Drug Abuse Interagency Agreement Y1DA-0107 supported the studies assessing the interaction of lobeline, lobelane, and MTD at the human neurotransmitter transporters expressed in HEK-293 cells. For purposes of full disclosure, the University of Kentucky holds patents on lobeline, which have been licensed by Yaupon Therapeutics, Inc. (Lexington, KY). A potential royalty stream to L.P.D. and P.A.C. may occur consistent with University of Kentucky policy, and both L.P.D. and P.A.C. 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.104.068098.

  • ABBREVIATIONS: DA, dopamine; DAT, DA transporter; VMAT2, vesicular monoamine transporter; SERT, serotonin transporter; nAChR, nicotinic receptor; 5-HT, serotonin; NE, norepinephrine; NET, NE transporter; MLA, methyllycaconitine; RTI-55, (-)-2β-carbomethoxy-3β-(4-iodophenyl)tropane; MTBZ, methoxytetrabenazine; BSA, bovine serum albumin; PEI, phenylethylenimine; TTX, tetrodotoxin; 10R-MESP, N-methyl-2R-(2R-hydroxy-2-phenylethyl)6S-(2-phenylethen-1-yl)piperidine; 10S/10R-MEPP, N-methyl-2R-(2R/2S-hydroxy-2-phenylethyl)6S-(2-phenylethyl)piperidine; MTD, mesotransdiene; TTD, trans-transdiene; GBR-12909, 1-(2-[bis(4-fluorophenyl)methoxy]ethyl)4-(3-phenylpropyl)piperazine; HEK, human embryonic kidney; SAR, structure-activity relationship.

  • ↵1 Current address: Department of Psychological Sciences, University of Missouri, Columbia, MO 65211.

  • ↵2 Current address: Targacept, Inc., 200 East First Street, Suite 300, Winston-Salem, NC 27101-4165.

  • ↵3 Current address: Department of Anatomy, College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd., MDC 6, Tampa, FL 33612-4799.

    • Received March 9, 2004.
    • Accepted April 28, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 310 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 310, Issue 3
1 Sep 2004
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Research ArticleNEUROPHARMACOLOGY

Lobeline Analogs with Enhanced Affinity and Selectivity for Plasmalemma and Vesicular Monoamine Transporters

Dennis K. Miller, Peter A. Crooks, Guangrong Zheng, Vladimir P. Grinevich, Seth D. Norrholm and Linda P. Dwoskin
Journal of Pharmacology and Experimental Therapeutics September 1, 2004, 310 (3) 1035-1045; DOI: https://doi.org/10.1124/jpet.104.068098

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Research ArticleNEUROPHARMACOLOGY

Lobeline Analogs with Enhanced Affinity and Selectivity for Plasmalemma and Vesicular Monoamine Transporters

Dennis K. Miller, Peter A. Crooks, Guangrong Zheng, Vladimir P. Grinevich, Seth D. Norrholm and Linda P. Dwoskin
Journal of Pharmacology and Experimental Therapeutics September 1, 2004, 310 (3) 1035-1045; DOI: https://doi.org/10.1124/jpet.104.068098
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