N-n-Alkylnicotinium Analogs, A Novel Class of Nicotinic Receptor Antagonist: Inhibition ofS(−)-Nicotine-Evoked [3H]Dopamine Overflow from Superfused Rat Striatal Slices

Biochemical Pharmacology

et al. 2007

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Limitations in efficacy and high relapse rates of currently available smoking cessation agents reveal the need for more efficacious pharmacotherapies. One strategy is to develop subtype-selective nicotinic receptor (nAChR) antagonists that inhibit nicotine-evoked dopamine (DA) release, the primary neurotransmitter involved in nicotine reward. Simple alkylation of the pyridino N-atom converts nicotine from a potent agonist into a potent antagonist. The classical antagonists, hexamethonium and decamethonium, differentiate between peripheral nAChR subtypes. Using a similar approach, we interconnected varying quaternary ammonium moieties with a lipophilic linker to provide N,N′-bis-nicotinium analogs, affording a lead compound, N,N′-dodecyl-1,12-diyl-bis-3-picolinium dibromide (bPiDDB), which inhibited nicotine-evoked DA release and decreased nicotine self-administration. The current work describes a novel compound, 1-(3-picolinium)-12-triethylammonium-dodecane dibromide (TMPD), a hybrid of bPiDDB and decamethonium. TMPD completely inhibited (IC 50 = 500 nM) nicotine-evoked DA release from superfused rat striatal slices, suggesting that TMPD acts as a nAChR antagonist at more than one subtype. TMPD (1 μM) inhibited the response to acetylcholine at α3β4, α4β4, α4β2, and α1β1εδ receptors expressed in Xenopus oocytes. TMPD had a 2-fold higher affinity for the blood-brain barrier choline transporter, suggesting that is brain bioavailable. TMPD did not inhibit the hyperactivity in nicotine sensitized rats, but significantly and specifically decreased nicotine self-administration. Together, the results suggest that TMPD may have the ability to reduce the rewarding effect of nicotine with minimal side effects, a pharmacological profile indicative of potential clinical utility for the treatment of tobacco dependence.

Section: [ 3 H]da Release Assaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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)

Dwoskin

Joyce

Biochemical Pharmacology

et al. 2007

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Bioorganic & Medicinal Chemistry Letters

Sumithran

Deaciuc

et al. 2007

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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...

“…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.…”

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confidence: 99%

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

Bioorganic & Medicinal Chemistry Letters

Zhang

Pivavarchyk

et al. 2007

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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...