Structure activity studies of ring E analogues of methyllycaconitine. Part 2: Synthesis of antagonists to the α3β4* nicotinic acetylcholine receptors through modifications to the ester

Bergmeier, Stephen C.; Ismail, Khadiga Ahmed; Arason, Kristjan M.; McKay, Susan B.; Bryant, Darrell L.; McKay, Dennis B.

doi:10.1016/j.bmcl.2004.05.001

Cited by 30 publications

(25 citation statements)

References 36 publications

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“…Although MLA itself is a competitive inhibitor of both native and recombinant (Free et al, 2003) ␣3␤4 nAChRs, our data support the inhibitory activity of several MLA analogs as noncompetitive in nature (Bergmeier et al, 1999(Bergmeier et al, , 2004Bryant et al, 2002). In the following studies, the concentration-response effects of 67 analogs of MLA on nicotine-stimulated adrenal neurosecretion were investigated ( Fig.…”

Section: Resultssupporting

confidence: 65%

“…1 and 9) were in general prepared by reaction of hydroxymethyl piperidine with the appropriate alkyl halide to provide the N-alkyl hydroxymethyl piperidine. This compound was then coupled to the appropriate carboxylic acid to provide the target MLA analog (Bergmeier et al, 2004). All compounds were pure as shown by 1 H NMR, 13 C NMR, and high-resolution mass spectrometry.…”

Section: Methodsmentioning

confidence: 99%

“…Taking this approach, our laboratory (Bergmeier et al, 1999(Bergmeier et al, , 2004Bryant et al, 2002) and others (Goodall et al, 2005) have synthesized analogs of MLA. Our laboratory has reported that these analogs seem to act as noncompetitive inhibitors of ␣3␤4* nAChRs based on their ability to inhibit nAChR-mediated neurosecretion without inhibition of agonist binding to nAChRs (Bergmeier et al, 1999(Bergmeier et al, , 2004Bryant et al, 2002).…”

mentioning

confidence: 99%

“…Our laboratory has reported that these analogs seem to act as noncompetitive inhibitors of ␣3␤4* nAChRs based on their ability to inhibit nAChR-mediated neurosecretion without inhibition of agonist binding to nAChRs (Bergmeier et al, 1999(Bergmeier et al, , 2004Bryant et al, 2002). In addition, these analogs had no effects on agonist binding to ␣4␤2 and ␣7 nAChRs (Bergmeier et al, 1999(Bergmeier et al, , 2004Bryant et al, 2002).…”

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confidence: 99%

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Analogs of Methyllycaconitine as Novel Noncompetitive Inhibitors of Nicotinic Receptors: Pharmacological Characterization, Computational Modeling, and Pharmacophore Development

McKay¹,

Chang²,

González-Cestari³

et al. 2007

Mol Pharmacol

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As a novel approach to drug discovery involving neuronal nicotinic acetylcholine receptors (nAChRs), our laboratory targeted nonagonist binding sites (i.e., noncompetitive binding sites, negative allosteric binding sites) located on nAChRs. Cultured bovine adrenal cells were used as neuronal models to investigate interactions of 67 analogs of methyllycaconitine (MLA) on native ␣3␤4* nAChRs. The availability of large numbers of structurally related molecules presents a unique opportunity for the development of pharmacophore models for noncompetitive binding sites. Our MLA analogs inhibited nicotinemediated functional activation of both native and recombinant ␣3␤4* nAChRs with a wide range of IC 50 values (0.9 -115 M). These analogs had little or no inhibitory effects on agonist binding to native or recombinant nAChRs, supporting noncompetitive inhibitory activity. Based on these data, two highly predictive 3D quantitative structure-activity relationship (comparative molecular field analysis and comparative molecular similarity index analysis) models were generated. These computational models were successfully validated and provided insights into the molecular interactions of MLA analogs with nAChRs. In addition, a pharmacophore model was constructed to analyze and visualize the binding requirements to the analog binding site. The pharmacophore model was subsequently applied to search structurally diverse molecular databases to prospectively identify novel inhibitors. The rapid identification of eight molecules from database mining and our successful demonstration of in vitro inhibitory activity support the utility of these computational models as novel tools for the efficient retrieval of inhibitors. These results demonstrate the effectiveness of computational modeling and pharmacophore development, which may lead to the identification of new therapeutic drugs that target novel sites on nAChRs.The physiological roles of neuronal nicotinic acetylcholine receptors (nAChRs) in synaptic release of acetylcholine and their involvement in the modulation of other important neurotransmitters such as norepinephrine, serotonin, GABA, glutamate, and dopamine make nAChRs prime targets for therapeutic interventions. In addition, nAChRs have been linked to pain, epilepsy, and many neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, and psychiatric disorders, such as depression and schizophrenia. The development of new drugs to target these receptors has been slow for several reasons: 1) multiple subtypes of nAChRs are expressed in the central and peripheral nervous systems; 2) few drugs are available that selectively target nAChR subtypes; and 3) information on the physiological roles of specific nAChR subtypes is limited. A key approach to provide a better understanding of physiological processes and pathophysiological conditions involving

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Section: Resultssupporting

confidence: 65%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Analogs of Methyllycaconitine as Novel Noncompetitive Inhibitors of Nicotinic Receptors: Pharmacological Characterization, Computational Modeling, and Pharmacophore Development

McKay¹,

Chang²,

González-Cestari³

et al. 2007

Mol Pharmacol

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“…35−37 This molecule was then coupled to the appropriate carboxylic acid to provide the target molecule. 36 All molecules were >98% pure as shown by 1 H NMR, 13 C NMR, and HRMS. All compounds were converted to their hydrochloride or oxalate salts.…”

Section: ■ Methodsmentioning

confidence: 87%

Defining the Putative Inhibitory Site for a Selective Negative Allosteric Modulator of Human α4β2 Neuronal Nicotinic Receptors

Henderson

González-Cestari

et al. 2012

ACS Chem. Neurosci.

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Neuronal nicotinic receptors (nAChRs) have been implicated in several diseases and disorders such as autism spectrum disorders, Alzheimer's disease, Parkinson's disease, epilepsy, and nicotine addiction. To understand the role of nAChRs in these conditions, it would be beneficial to have selective molecules that target specific nAChRs in vitro and in vivo. Our laboratory has previously identified a novel allosteric site on human α4β2 nAChRs using a series of computational and in vitro approaches. At this site, we have identified negative allosteric modulators that selectively inhibit human α4β2 nAChRs, a subtype implicated in nicotine addiction. This study characterizes the allosteric site via site-directed mutagenesis. Three amino acids (Phe118, Glu60, and Thr58) on the β2 subunit were shown to participate in the inhibitory properties of the selective antagonist KAB-18 and provided insights into its antagonism of human α4β2 nAChRs. SAR studies with KAB-18 analogues and various mutant α4β2 nAChRs also provided information concerning how different physiochemical features influence the inhibition of nAChRs through this allosteric site. Together, these studies identify the amino acids that contribute to the selective antagonism of human α4β2 nAChRs at this allosteric site. Finally, these studies define the physiochemical features of ligands that influence interaction with specific amino acids in this allosteric site.

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Double Ring‐Expanding Carbonylation Using an In Situ Generated Aluminum Phthalocyanine Cobalt Carbonyl Complex

2018

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The ring-expanding carbonylation of epoxides provides an efficient one-step procedure for synthesizing βlactones and succinic anhydride derivatives. Although porphyrin-based catalysts generally show excellent catalytic activities in the ring-expanding carbonylation of epoxides, the application of porphyrin catalysts is limited owing to the low yield and high cost of preparing porphyrins. This study aims to propose a new and highly efficient catalytic system for the carbonylation of propylene oxide (PO) using an in situ generated active catalyst from cost-effective and readily available aluminum phthalocyanine chloride (AlPcCl) and dicobalt octacarbonyl (Co 2 (CO) 8 ). The catalyst showed not only excellent catalytic activities of single carbonylation but also double carbonylation resulting in anhydride by judicious choice of reaction parameters, such as reaction temperature and the ratio of PO to catalyst. This is the first report on the use of an in situ generated catalyst for the one-pot double carbonylation of epoxide to anhydride.[a] Dr.

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Structure activity studies of ring E analogues of methyllycaconitine. Part 2: Synthesis of antagonists to the α3β4* nicotinic acetylcholine receptors through modifications to the ester

Cited by 30 publications

References 36 publications

Analogs of Methyllycaconitine as Novel Noncompetitive Inhibitors of Nicotinic Receptors: Pharmacological Characterization, Computational Modeling, and Pharmacophore Development

Analogs of Methyllycaconitine as Novel Noncompetitive Inhibitors of Nicotinic Receptors: Pharmacological Characterization, Computational Modeling, and Pharmacophore Development

Defining the Putative Inhibitory Site for a Selective Negative Allosteric Modulator of Human α4β2 Neuronal Nicotinic Receptors

Double Ring‐Expanding Carbonylation Using an In Situ Generated Aluminum Phthalocyanine Cobalt Carbonyl Complex

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