Discovery of a novel nicotinic receptor antagonist for the treatment of nicotine addiction: 1-(3-Picolinium)-12-triethylammonium-dodecane dibromide (TMPD)

Dwoskin, Linda P.; Joyce, B. Matthew; Zheng, Guangrong; Neugebauer, Nichole M.; Manda, Vamshi K.; Lockman, Paul R.; Papke, Roger L.; Bardo, Michael T.; Crooks, Peter A.

doi:10.1016/j.bcp.2007.07.021

Cited by 9 publications

(5 citation statements)

References 77 publications

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“…Therefore in ligand discovery for nicotinic compounds there is the opportunity to evaluate chemical entities across a large assembly of potential 'screening' measures of increasing complexity, a fact which should tilt the balance in favor of early decisions regarding a given entity and yield, at the least, novel research tools with defined profiles of actions. Translational research to this extent can be achieved by researchers in academic settings, and is happening to a limited extent for nAChR ligands (see example [198][199][200][201][202][203]). …”

Section: Application Models To the Drug Discovery Process For Nicotinmentioning

confidence: 99%

Neuronal Nicotinic Receptors as Brain Targets for Pharmacotherapy of Drug Addiction

Rahman¹,

López-Hernández²,

Corrigall³

et al. 2008

CNSNDDT

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Nicotine addiction and other forms of drug addiction continue to be significant public health problems in the United States and the rest of the world. Accumulated evidence indicates that brain nicotinic acetylcholine receptors (nAChRs) are a heterogenous family of ion channels expressed in the various parts of the brain. A growing body of preclinical studies suggests that brain nAChRs are critical targets for the development of pharmacotherapies for nicotine and other drug addictions. In this review, we will discuss the nAChR subtypes, their function in response to endogenous brain transmitters, and how their functions are regulated in the presence of nicotine. Furthermore, we will discuss the role of nAChRs in mediating nicotine-induced addictive behavior in animal models. Additionally, we will provide an overview of the effects of nicotine and nicotinic compounds on the mesolimbic dopamine system, part of the reinforcement/reward circuitry of the brain, as an example of the neurochemical basis of nicotine addiction and other drug addictions. An appreciation of the complexity of nicotinic receptors and their regulation will be necessary for the development of nicotinic receptor modulators as potential pharmacotherapy for drug addiction.

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Section: Application Models To the Drug Discovery Process For Nicotinmentioning

confidence: 99%

Neuronal Nicotinic Receptors as Brain Targets for Pharmacotherapy of Drug Addiction

Rahman¹,

López-Hernández²,

Corrigall³

et al. 2008

CNSNDDT

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“…IC 50 and Imax values of inhibition of nicotine-evoked [ 3 H]DA release were determined using 10 μM NIC and a full concentration range (1 nM to 10 μM) of analogue, and then calculated using an iterative nonlinear least squares curve-fitting program, PRISM version 4.0 (GraphPAD Software, Inc., San Diego, CA). 33 All the analogues in the 3 and 4 series with the exception of the tris-nicotinium compounds exhibited low or no affinity at α4β2* nAChRs probed by [ 3 H]NIC binding. tris-Nicotinium compounds in both the 3 and 4 series (3f and 4f, respectively) displayed significant potency at α4β2*, affording 44% and 88% inhibition, respectively.…”

mentioning

confidence: 98%

“…[ 3 H]DA release assays were performed according to a previously published method. 33 Analogueinduced inhibition of nicotine-evoked [ 3 H]DA release was determined using 10 μM NIC and 100 nM analogue concentrations. Amount of inhibition is presented as a percentage of the response to nicotine under control conditions (in the absence of analogue) and the values are provided in Table 1.…”

mentioning

confidence: 99%

tris-Azaaromatic quaternary ammonium salts: Novel templates as antagonists at nicotinic receptors mediating nicotine-evoked dopamine release

Zheng

Sumithran

Deaciuc

et al. 2007

Bioorganic & Medicinal Chemistry Letters

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A series of tris-azaaromatic quaternary ammonium salts has been synthesized and evaluated for their ability to inhibit neuronal nicotinic acetylcholine receptors (nAChRs) mediating nicotineevoked [ 3 H]dopamine release from superfused rat striatal slices and for inhibition of [ 3 H]nicotine and [ 3 H]methyllycaconitine binding to whole rat brain membranes. The 3-picolinium compound 1,3,5-tri-{5-[1-(3-picolinium)]-pent-1-ynyl}benzene tribromide (tPy3PiB), 3b exhibited high potency and selectivity for nAChR subtypes mediating nicotine-evoked [ 3 H]dopamine release with an IC 50 of 0.2 nM and Imax of 67%.Neuronal nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels composed of five (α and/or β) subunits, each spanning the membrane four times and aligning around the central ion channel. [1][2][3] To date, ten α (α1-α10) and four β (β1-β4) subunits have been identified. 4 Combinations of different subunits establish the various nAChR subtypes, and have distinct pharmacological profiles. 5,6 Activation of specific subtypes of nAChRs contributes to the reinforcing effects of nicotine by stimulating release of the neurotransmitter dopamine (DA). 7-13 Nicotine-evoked DA release is calciumdependent and is blocked completely by the classical nAChR inhibitors, mecamylamine and DHβE, demonstrating that this effect is a direct action at nAChRs. 10 Subtype-selective nAChR antagonists which inhibit nicotine-evoked DA release, have been proposed as potential therapeutic agents for nicotine addiction. [14][15][16][17] To date, the nAChR subtype(s) mediating nicotine-evoked DA release and the mechanism of inhibition of the inhibitors at this receptor subtype have not been elucidated conclusively. Also, in contrast to extensive research on subtype-selective nAChR agonists, less attention has focused on the development of subtype-selective nAChR antagonists. 16,17 The availability of subtypeselective nAChR antagonists would augment the identification of the antagonist pharmacophore(s) for the nAChR subtype(s) mediating nicotine-evoked DA release. Moreover, such subtype-selective antagonists may have potential as treatments for nicotine dependence.© 2007 Elsevier Ltd. All rights reserved.Correspondence to: Peter A. Crooks. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Previous studies from our laboratories have identified N,N '-dodecane-1,12-diyl-bis-3picolinium dibromide (bPiDDB; 1; Figure 1) as a potent inhibitor (IC 50 = 5 nM) of nAChRs mediating nicotine-evoked [ 3 H]DA release from superfused rat striatal slices. 18,19 In vivo microdialysis studies...

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“…30 Analogues were evaluated at a probe concentration of 100 nM. The amount of inhibition is presented as a percentage of radioligand binding in the absence of analogue (control, Table 1).…”

mentioning

confidence: 99%

“…Analogue-induced inhibition of nicotine-evoked [ 3 H]DA release was determined using 10 μM nicotine and 100 nM analogue. 30 Inhibition is presented as a percentage of the response to nicotine under control conditions (in the absence of analogue) and the values are provided in Table 1.…”

mentioning

confidence: 99%

Bis-azaaromatic quaternary ammonium salts as antagonists at nicotinic receptors mediating nicotine-evoked dopamine release: An investigation of binding conformation

Zheng

Zhang

Pivavarchyk

et al. 2007

Bioorganic & Medicinal Chemistry Letters

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A series of conformationally restricted bis-azaaromatic quaternary ammonium salts (3 and 4) have been designed and synthesized in order to investigate the possible binding conformations of N,N′-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB; 2), a compound which potently inhibits neuronal nicotinic acetylcholine receptors (nAChRs) mediating nicotine-evoked dopamine release. The preliminary structure-activity relationships of these new analogues suggest that bPiDDB binds in an extended conformation at the nAChR binding site, and that flexibility of the linker may be important for its high potency in inhibiting nAChRs mediating nicotine-evoked dopamine release. KeywordsNicotinic acetylcholine receptor; Quaternary ammonium; Dopamine release; Nicotine addiction Tobacco contains one of the most widely abused psychoactive substances in the world, that is, (S)-nicotine (1; Fig. 1), which is believed to be primarily responsible for tobacco dependence. 1,2 Like many abused drugs, nicotine addiction has been linked to the release of the neurotransmitter, dopamine (DA). [3][4][5] Nicotine-evoked DA release, which is thought to be responsible for reward, leading to addiction, is believed to result from activation of presynaptic neuronal nicotinic acetylcholine receptors (nAChRs). [6][7][8][9][10][11][12] Nicotine stimulates all known nAChR subtypes 13 and upon activation, these receptors modulate the release of various neurotransmitters. [14][15][16] The subunit composition of nAChR subtypes responsible for mediating nicotine-evoked DA release has not been elucidated conclusively. 17 In this regard, subtype-selective nAChR antagonists, which inhibit nicotine-evoked DA release, may have potential as novel treatments for nicotine addiction. [18][19][20][21] Previous work in our laboratories has led to the discovery of N, N′-dodecane-1,12-diyl-bis-3picolinium dibromide (bPiDDB; 2; Fig. 1), which potently inhibited nAChR subtype(s) mediating nicotine-evoked [ 3 H]DA release from superfused rat striatal slices in vitro (IC 50 = 5 nM), and did not interact at the ligand binding site of either α4β2 * or α7 * nAChRs. 22,23 In vivo microdialysis studies demonstrated that pretreatment with bPiDDB dose-dependently reduced the increase in extracellular DA in rat nucleus accumbens produced by acute or repeated nicotine treatment. 24 nature and polarity of the molecule, bPiDDB is brain bioavailable, due to its facilitated transport via the blood-brain barrier choline transporter. 25 Moreover, behavioral studies in rats showed that bPiDDB dose-dependently decreased intravenous nicotine selfadministration, but not sucrose-maintained responding, suggesting a specific inhibition of nicotine reward. 26 Taken together, bPiDDB and its analogues represent lead compounds for the development of a new class of therapeutic agents for the treatment of tobacco dependence.bPiDDB (2) contains two 3-picolinium head groups connected via an N-N-12-methylene linker unit; thus, it is a highly flexible, di-cationic molecule. A better understan...

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Discovery of a novel nicotinic receptor antagonist for the treatment of nicotine addiction: 1-(3-Picolinium)-12-triethylammonium-dodecane dibromide (TMPD)

Cited by 9 publications

References 77 publications

Neuronal Nicotinic Receptors as Brain Targets for Pharmacotherapy of Drug Addiction

Neuronal Nicotinic Receptors as Brain Targets for Pharmacotherapy of Drug Addiction

tris-Azaaromatic quaternary ammonium salts: Novel templates as antagonists at nicotinic receptors mediating nicotine-evoked dopamine release

Bis-azaaromatic quaternary ammonium salts as antagonists at nicotinic receptors mediating nicotine-evoked dopamine release: An investigation of binding conformation

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