Development of subtype-selective ligands as antagonists at nicotinic receptors mediating nicotine-evoked dopamine release

Crooks, Peter A.; Ayers, Joshua T.; Xu, Rui; Sumithran, Sangeetha P.; Grinevich, Vladimir P.; Wilkins, Lincoln H.; Deaciuc, Agripina G.; Allen, David; Dwoskin, Linda P.

doi:10.1016/j.bmcl.2003.10.074

Cited by 30 publications

(45 citation statements)

References 27 publications

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“…Selective nAChR agonists/antagonists have therapeutic potential in the treatment of Alzheimer's disease, Parkinson's disease, dyskinesias, Tourette's syndrome, schizophrenia, attention deficit disorder, anxiety, and pain, as well as tobacco-use cessation agents. 19,23,26,27,28,29,30,31,32,33 Each of these biologically important amine compounds has a protonable amine moiety and, therefore, has both the protonated and deprotonated molecular species in aqueous solution. It has been known that both the protonated and deprotonated molecular species could bind with a protein.…”

Section: Introductionmentioning

confidence: 99%

First-Principles Calculation of pK_a for Cocaine, Nicotine, Neurotransmitters, and Anilines in Aqueous Solution

Chen

2007

J. Phys. Chem. B

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The absolute pK a values of 24 representative amine compounds, including cocaine, nicotine, 10 neurotransmitters, and 12 anilines, in aqueous solution were calculated by performing first-principles electronic structure calculations that account for the solvent effects using four different solvation models, i.e. the surface and volume polarization for electrostatic interaction (SVPE) model, the standard polarizable continuum model (PCM), the integral equation formalism for the polarizable continuum model (IEFPCM), and the conductor-like screening solvation model (COSMO). Within the examined computational methods, the calculations using the SVPE model lead to the absolute pK a values with the smallest root-mean-square-deviation (RMSD) value (1.18). When the SVPE model was replaced by the PCM, IEFPCM, and COSMO, the RMSD value of the calculated absolute pK a values became 3.21, 2.72, and 3.08, respectively. All types of calculated pK a values linearly correlate with the experimental pK a values very well. With the empirical corrections using the linear correlation relationships, the theoretical pK a values are much closer to the corresponding experimental data and the RMSD values become 0.51 to 0.83. The smallest RMSD value (0.51) is also associated with the SVPE model. All of the results suggest that the first-principles electronic structure calculations using the SVPE model are a reliable approach to the pK a prediction for the amine compounds.

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Section: Introductionmentioning

confidence: 99%

First-Principles Calculation of pK_a for Cocaine, Nicotine, Neurotransmitters, and Anilines in Aqueous Solution

Chen

2007

J. Phys. Chem. B

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“…These results with the nicotinium analogues are consistent with our previous results with mono-nicotinium and bis-nicotinium analogues. 19,30,34 Several analogues, i.e., 3g, 3i, 3j, and 4i, displayed some potency at α7* nAChRs. Notably, all of these four analogues bear bulky, more hydrophobic cationic head groups.…”

Section: Nih Public Accessmentioning

confidence: 99%

“…In initial studies, a series of mono-azaaromatic quaternary ammonium compounds was synthesized and assessed for activity in the nicotine-evoked [ 3 H]DA release assay. 18,30 From these studies, N-n-dodecyl-3-picolinium iodide (NDDPiI; 2; Figure 1), a compound containing only one cationic head group rather than the two cationic head groups in the bPiDDB molecule, inhibited nicotine-evoked [ 3 H]DA release with an IC 50 of 30 nM and an Imax of 62%. 18 Taken together, these results suggest that the second positively charged picolinium head group increased the affinity, but did not appear to change the selectivity for specific nAChRs mediating nicotine-evoked DA release.…”

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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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“…However, some of the analogues which contained nicotinium head groups, i.e., compounds 3ad and 4ad, displayed considerable affinity at α4β2 * , which is consistent with the results obtained with our previously reported mononicotinium and bis-nicotinium analogues. 22,31 Among the analogues of general structure 3 (Scheme 1), the 1,2-isomers (3a), including compounds 3aa, 3ab, and 3ac, exhibited significantly lower potency for inhibition of nicotine-evoked [ 3 H]DA release than the 1,3-and 1,4-isomers (3b and 3c), including compounds 3ba, 3bb, 3bc, 3ca, 3cb, and 3cc. The 1,3-and 1,4-picolinium analogues all had similar potency.…”

Section: Introductionmentioning

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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Development of subtype-selective ligands as antagonists at nicotinic receptors mediating nicotine-evoked dopamine release

Cited by 30 publications

References 27 publications

First-Principles Calculation of pK_a for Cocaine, Nicotine, Neurotransmitters, and Anilines in Aqueous Solution

First-Principles Calculation of pK_a for Cocaine, Nicotine, Neurotransmitters, and Anilines in Aqueous Solution

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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Development of subtype-selective ligands as antagonists at nicotinic receptors mediating nicotine-evoked dopamine release

Cited by 30 publications

References 27 publications

First-Principles Calculation of pKa for Cocaine, Nicotine, Neurotransmitters, and Anilines in Aqueous Solution

First-Principles Calculation of pKa for Cocaine, Nicotine, Neurotransmitters, and Anilines in Aqueous Solution

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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First-Principles Calculation of pK_a for Cocaine, Nicotine, Neurotransmitters, and Anilines in Aqueous Solution

First-Principles Calculation of pK_a for Cocaine, Nicotine, Neurotransmitters, and Anilines in Aqueous Solution