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a complex consisting of an organic base in association with hydrogen chloride

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1. 変形性関節症の初回薬物療法 initial pharmacologic therapy of osteoarthritis
2. 過敏性腸症候群に対するアロセトロン塩酸塩（Lotronex） alosetron hydrochloride lotronex for irritable bowel syndrome
3. クリンダマイシン：概要 clindamycin an overview
4. 成人における急性咽頭炎の対症療法 symptomatic treatment of acute pharyngitis in adults
5. 慢性非アレルギー性鼻炎 chronic nonallergic rhinitis

English Journal

Evaluation of mutagenic and genotoxic activities of lobeline and its modulation on genomic instability induced by ethanol.

da Costa E Silva LD1, Rodrigues LC1, Dos Santos VR1, da Costa Allgayer M2, de Barros Falcão Ferraz A3, Rolla HC4, Pereira P5, Picada JN6.Author information 1Laboratório de Genética Toxicológica, Universidade Luterana do Brasil, Canoas, RS, Brazil.2Laboratório de Patologia Clínica, Hospital Veterinário, Universidade Luterana do Brasil, Canoas, RS, Brazil.3Laboratório de Fitoquímica, Universidade Luterana do Brasil, Canoas, RS, Brazil.4Bioensaios Análises e Consultoria Ambiental, Viamão, RS, Brazil.5Departamento de Farmacologia, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.6Laboratório de Genética Toxicológica, Universidade Luterana do Brasil, Canoas, RS, Brazil. Electronic address: jnpicada@cpovo.net.AbstractAIM: Lobeline is a natural alkaloid derived from Lobelia inflata that has been investigated as a clinical candidate for the treatment of alcoholism. In a pre-clinical trial, lobeline decreased the preference for and consumption of ethanol, due to the modulation of the nicotinic acetylcholine receptor. However, the interaction between lobeline and ethanol is poorly known and thus there are safety concerns. The present study was conducted to evaluate the mutagenic and genotoxic effects of lobeline and assess its modulation of ethanol-induced toxicological effects.
Life sciences.Life Sci.2014 Apr 12. pii: S0024-3205(14)00388-9. doi: 10.1016/j.lfs.2014.03.034. [Epub ahead of print]
AIM: Lobeline is a natural alkaloid derived from Lobelia inflata that has been investigated as a clinical candidate for the treatment of alcoholism. In a pre-clinical trial, lobeline decreased the preference for and consumption of ethanol, due to the modulation of the nicotinic acetylcholine recepto
PMID 24727238

Effects of VMAT2 inhibitors lobeline and GZ-793A on methamphetamine-induced changes in dopamine release, metabolism and synthesis in vivo.

Meyer AC1, Neugebauer NM, Zheng G, Crooks PA, Dwoskin LP, Bardo MT.Author information 1Department of Psychiatry, University of Vermont, Burlington, Vermont, USA.AbstractVesicular monoamine transporter-2 (VMAT2) inhibitors reduce methamphetamine (METH) reward in rats. The current study determined the effects of VMAT2 inhibitors lobeline (LOB; 1 or 3 mg/kg) and N-(1,2R-dihydroxylpropyl)-2,6-cis-di(4-methoxyphenethyl)piperidine hydrochloride (GZ-793A; 15 or 30 mg/kg) on METH-induced (0.5 mg/kg, SC) changes in extracellular dopamine (DA) and its metabolite dihydroxyphenylacetic acid (DOPAC) in the reward-relevant nucleus accumbens (NAc) shell using in vivo microdialysis. The effect of GZ-793A (15 mg/kg) on DA synthesis in tissue also was investigated in NAc, striatum, medial prefrontal cortex and orbitofrontal cortex. In NAc shell, METH produced a time-dependent increase in extracellular DA and decrease in DOPAC. Neither LOB nor GZ-793A alone altered extracellular DA; however, both drugs increased extracellular DOPAC. In combination with METH, LOB did not alter the effects of METH on DA; however, GZ-793A, which has greater selectivity than LOB for inhibiting VMAT2, reduced the duration of the METH-induced increase in extracellular DA. Both LOB and GZ-793A enhanced the duration of the METH-induced decrease in extracellular DOPAC. METH also increased tissue DA synthesis in NAc and striatum, whereas GZ-793A decreased synthesis; no effect of METH or GZ-793A on DA synthesis was found in medial prefrontal cortex or orbitofrontal cortex. These results suggest that selective inhibition of VMAT2 produces a time-dependent decrease in DA release in NAc shell as a result of alterations in tyrosine hydroxylase activity, which may play a role in the ability of GZ-793A to decrease METH reward.
Journal of neurochemistry.J Neurochem.2013 Oct;127(2):187-98. doi: 10.1111/jnc.12373. Epub 2013 Aug 20.
Vesicular monoamine transporter-2 (VMAT2) inhibitors reduce methamphetamine (METH) reward in rats. The current study determined the effects of VMAT2 inhibitors lobeline (LOB; 1 or 3 mg/kg) and N-(1,2R-dihydroxylpropyl)-2,6-cis-di(4-methoxyphenethyl)piperidine hydrochloride (GZ-793A; 15 or 30 mg/kg)
PMID 23875705

Phenyl ring-substituted lobelane analogs: inhibition of [³H]dopamine uptake at the vesicular monoamine transporter-2.

Nickell JR1, Zheng G, Deaciuc AG, Crooks PA, Dwoskin LP.Author information 1Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA.AbstractLobeline attenuates the behavioral effects of methamphetamine via inhibition of the vesicular monoamine transporter (VMAT2). To increase selectivity for VMAT2, chemically defunctionalized lobeline analogs, including lobelane, were designed to eliminate nicotinic acetylcholine receptor affinity. The current study evaluated the ability of lobelane analogs to inhibit [³H]dihydrotetrabenazine (DTBZ) binding to VMAT2 and [³H]dopamine (DA) uptake into isolated synaptic vesicles and determined the mechanism of inhibition. Introduction of aromatic substituents in lobelane maintained analog affinity for the [³H]DTBZ binding site on VMAT2 and inhibitory potency in the [³H]DA uptake assay assessing VMAT2 function. The most potent (K(i) = 13-16 nM) analogs in the series included para-methoxyphenyl nor-lobelane (GZ-252B), para-methoxyphenyl lobelane (GZ-252C), and 2,4-dichlorphenyl lobelane (GZ-260C). Affinity of the analogs for the [³H]DTBZ binding site did not correlate with inhibitory potency in the [³H]DA uptake assay. It is noteworthy that the N-benzylindole-, biphenyl-, and indole-bearing meso-analogs 2,6-bis[2-(1-benzyl-1H-indole-3-yl)ethyl]-1-methylpiperidine hemifumarate (AV-1-292C), 2,6-bis(2-(biphenyl-4-yl)ethyl)piperidine hydrochloride (GZ-272B), and 2,6-bis[2-(1H-indole-3-yl)ethyl]-1-methylpiperidine monofumarate (AV-1-294), respectively] inhibited VMAT2 function (K(i) = 73, 127, and 2130 nM, respectively), yet had little to no affinity for the [³H]DTBZ binding site. These results suggest that the analogs interact at an alternate site to DTBZ on VMAT2. Kinetic analyses of [³H]DA uptake revealed a competitive mechanism for 2,6-bis(2-(4-methoxyphenyl)ethyl)piperidine hydrochloride (GZ-252B), 2,6-bis(2-(4-methoxyphenyl)ethyl)-1-methylpiperidine hydrochloride (GZ-252C), 2,6-bis(2-(2,4-dichlorophenyl)ethyl)piperidine hydrochloride (GZ-260C), and GZ-272B. Similar to methamphetamine, these analogs released [³H]DA from the vesicles, but with higher potency. In contrast to methamphetamine, these analogs had higher potency (>100-fold) at VMAT2 than DAT, predicting low abuse liability. Thus, modification of the lobelane molecule affords potent, selective inhibitors of VMAT2 function and reveals two distinct pharmacological targets on VMAT2.
The Journal of pharmacology and experimental therapeutics.J Pharmacol Exp Ther.2011 Mar;336(3):724-33. doi: 10.1124/jpet.110.172882. Epub 2010 Sep 28.
Lobeline attenuates the behavioral effects of methamphetamine via inhibition of the vesicular monoamine transporter (VMAT2). To increase selectivity for VMAT2, chemically defunctionalized lobeline analogs, including lobelane, were designed to eliminate nicotinic acetylcholine receptor affinity. The
PMID 20876747