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

Zheng, Guangrong; Zhang, Zhenfa; Pivavarchyk, Marharyta; Deaciuc, Agripina G.; Dwoskin, Linda P.; Crooks, Peter A.

doi:10.1016/j.bmcl.2007.10.052

Cited by 12 publications

(12 citation statements)

References 25 publications

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“…13.6A) and the l,3,5-tri-( n -pentanyl-5-azaaromatic quaternary ammonium) benzene series (scaffold B, saturated) (Fig. 13.6B) (Zheng, Zhang, et al, 2007). The tris-azaaromatic quaternary ammonium salts were synthesized utilizing Sonogashira coupling chemistry (Fig.…”

Section: Monoquaternary Ammonium Salts Derived From N-methylnicotimentioning

confidence: 99%

Nicotinic Receptor Antagonists as Treatments for Nicotine Abuse

Crooks

Bardo

Dwoskin

2014

Advances in Pharmacology

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Despite the proven efficacy of current pharmacotherapies for tobacco dependence, relapse rates continue to be high, indicating that novel medications are needed. Currently, several smoking cessation agents are available, including varenicline (Chantix®), bupropion (Zyban®), and cytisine (Tabex®). Varenicline and cytisine are partial agonists at the α4β2* nicotinic acetylcholine receptor (nAChR). Bupropion is an antidepressant but is also an antagonist at α3β2* ganglionic nAChRs. The rewarding effects of nicotine are mediated, in part, by nicotine-evoked dopamine (DA) release leading to sensitization, which is associated with repeated nicotine administration and nicotine addiction. Receptor antagonists that selectivity target central nAChR subtypes mediating nicotine-evoked DA release should have efficacy as tobacco use cessation agents with the therapeutic advantage of a limited side-effect profile. While α-conotoxin MII (α-CtxMII)-insensitive nAChRs (e.g., α4β2*) contribute to nicotine-evoked DA release, these nAChRs are widely distributed in the brain, and inhibition of these receptors may lead to nonselective and untoward effects. In contrast, α-CtxMII-sensitive nAChRs mediating nicotine-evoked DA release offer an advantage as targets for smoking cessation, due to their more restricted localization primarily to dopaminergic neurons. Small drug-like molecules that are selective antagonists at α-CtxMII-sensitive nAChR subtypes that contain α6 and β2 subunits have now been identified. Early research identified a variety of quaternary ammonium analogs that were potent and selective antagonists at nAChRs mediating nicotine-evoked DA release. More recent data have shown that novel, non-quaternary bis-1,2,5,6-tetrahydropyridine analogs potently inhibit (IC50<1 nM) nicotine-evoked DA release in vitro by acting as antagonists at α-CtxMII-sensitive nAChR subtypes; these compounds also decrease NIC self-administration in rats.

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Section: Monoquaternary Ammonium Salts Derived From N-methylnicotimentioning

confidence: 99%

Nicotinic Receptor Antagonists as Treatments for Nicotine Abuse

Crooks

Bardo

Dwoskin

2014

Advances in Pharmacology

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“…Tris-and tetrakis-AQA analogs were prepared as described previously (Zheng et al, 2007;Dwoskin et al, 2008). PNU-120596 was purchased from Tocris (Ellisville, MO).…”

Section: Methodsmentioning

confidence: 99%

Selective Inhibition of Acetylcholine-Evoked Responses of α7 Neuronal Nicotinic Acetylcholine Receptors by Novel tris- and tetrakis-Azaaromatic Quaternary Ammonium Antagonists

et al. 2009

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A family of 20 tris-azaaromatic quaternary ammonium (AQA) compounds were tested for their inhibition of ␣7 nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus laevis oocytes. The potency of inhibitory activity was related to the hydrophobic character of the tris head groups. Two tris-AQA compounds were studied in detail: the highly effective inhibitor 1,3,5-tri-[5-(1-quinolinum)-pent-1-yn-1-yl]-benzene tribromide (tPyQB) and the less potent antagonist 1,3,5,-tri-{5-[1-(2-picolinium)]-pent-1-yn-1-yl}benzene tribromide (tPy2PiB). In addition, we evaluated 1,2,4,5-tetra-{5-[1-(3-benzyl)pyridinium]pent-1-yl}benzene tetrabromide (tkP3BzPB), a tetrakis-AQA with very hydrophobic headgroups. We compared the activity of the AQA compounds to the frequently used ␣7-antagonist methyllycaconitine (MLA). Both tPyQB and tkP3BzPB were selective antagonists of ␣7. However, although inhibition by tPyQB was reversible within 5 min, the recovery time constant for tkP3BzPB inhibition was 26.6 Ϯ 0.8 min, so that the equilibrium inhibition in the prolonged presence of nanomolar concentrations of tkP3BzPB was nearly 100%. The potency, selectivity, and slow reversibility of tkP3BzPB were comparable with or greater than that of MLA. The inhibitory actions of tPyQB, tPy2PiB, and tkP3BzPB were evaluated on the acetylcholine (ACh)-evoked responses of native nAChRs in rat brain slices. The ␣7-mediated responses of hippocampal interneurons were effectively reduced by 1 M tPyQB and tkP3BzPB but not tPy2PiB. In rat medial septum, tkP3BzPB produced a greater inhibition of ACh-evoked responses of cells with fast inward currents (type I) than of cells with predominantly slow kinetics (type II), suggesting that tkP3BzPB can block ␣7 yet preserve the responsiveness of non-␣7 receptors. These agents might be helpful in elucidating complex receptor responses in brain regions with mixed populations of nAChRs.Nicotinic acetylcholine receptors (nAChRs) are distributed throughout the central and peripheral nervous systems (Role and Berg, 1996;Wonnacott, 1997). Nine neuronal ␣ subunits (␣2-␣10) and three neuronal ␤ subunits (␤2-␤4) have thus far been identified and cloned in vertebrate systems. One type of neuronal nAChR is formed by the assembly of ␣ and ␤ subunits, with functional properties depending on both ␣ and ␤ subunits within the receptor complex (Buisson and Bertrand, 2002). In Xenopus laevis oocytes, pairwise combinations of some neuronal ␣ and ␤ subunits form functional receptors. However, the existence of complex subtypes consisting of more than two different subunits has been documented in native brain regions. In addition to the heteromeric recep-

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“…2), which incorporate a benzene ring and two triple bonds into the middle of the N-N′ linker unit, thereby constraining these molecules into an extended or angular geometry, could served as model compounds for the purpose of this study. 22 …”

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confidence: 99%

“…22 Analogs 15-17 were prepared in the same manner as analogs 13 and 14 utilizing the appropriate azaaromatic headgroup precursors.…”

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Bis-azaaromatic quaternary ammonium salts as ligands for the blood–brain barrier choline transporter

Zheng

Zhang

Lockman

et al. 2010

Bioorganic & Medicinal Chemistry Letters

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A series of bis-azaaromatic quaternary ammonium compounds containing flexible polymethylenic linkers as well as conformationally restricted linkers were evaluated for their affinity for the blood-brain barrier choline transporter (BBB-ChT). The preliminary structure-activity relationships obtained from this study suggest that incorporating a linear, conformationally restricted linker into the molecule improves affinity for the BBB-ChT.

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

Cited by 12 publications

References 25 publications

Nicotinic Receptor Antagonists as Treatments for Nicotine Abuse

Nicotinic Receptor Antagonists as Treatments for Nicotine Abuse

Selective Inhibition of Acetylcholine-Evoked Responses of α7 Neuronal Nicotinic Acetylcholine Receptors by Novel tris- and tetrakis-Azaaromatic Quaternary Ammonium Antagonists

Bis-azaaromatic quaternary ammonium salts as ligands for the blood–brain barrier choline transporter

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