Discovery of benzamide analogs as negative allosteric modulators of human neuronal nicotinic receptors: Pharmacophore modeling and structure–activity relationship studies

Yi, B; Long, Sihui; González-Cestari, Tatiana F.; Henderson, Brandon J.; Pavlovicz, Ryan E.; Werbovetz, Karl A.; Li, Chenglong; McKay, Dennis B.

doi:10.1016/j.bmc.2013.03.082

Cited by 7 publications

(10 citation statements)

References 28 publications

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“…NMR was used to monitor the progress of the allylation reaction (Figure and Figures S1–S6; data obtained on aSA and a4HBA were discussed in ref ), which are agreement with prior literature. − The 1 H NMR spectra of all allylated phenolic acids show the disappearance of peaks located in the range of 8–14 ppm associated with the carboxyl and hydroxyl groups in the phenolic acids. The peaks located in the region of 4–6 ppm correspond to the allyl groups in the allylated phenolic acids.…”

Section: Resultssupporting

confidence: 82%

Thiol–Ene Elastomers Derived from Biobased Phenolic Acids with Varying Functionality

et al. 2016

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The synthesis and physical properties of thiol− ene elastomers derived from plant-based phenolic acids were explored. Phenolic acids of varying functionality (ranging from 2 to 4 hydroxyl and carboxyl groups per molecule) and relative placement of functional groups (ortho, meta, para) were allylated and subsequently reacted with a multifunctional thiol using a photoinitiator. The thermal and mechanical behaviors of the resulting elastomers were characterized. The networks derived from difunctional allylated phenolic acids exhibited narrow glass transitions (indicating a high degree of network homogeneity) and glass transition temperatures (T g ) which correlated with their cross-link density. The para placement of allyl groups on the allylated phenolic acid produced a network with the highest cross-link density, T g , modulus, tensile strength, and elongation at break (followed by ortho and then meta). As the functionality of the allylated monomer increased (to 3−4 allyl groups per molecule), the cross-link density remained high yet the T g decreased, attributed to a lower concentration of benzene rings throughout the network structure (as all networks were prepared at the stoichiometric ratio of allyl and thiol functional groups). The networks derived from the higher functionality allylated phenolic acids also exhibited lower elongation at break and associated tensile strength and tensile toughness, likely due to increased heterogeneity of the networks (indicated by higher glass transition widths compared to the networks derived from difunctional allylated phenolic acids). All networks exhibited behavior consistent with an ideal elastomer (affine network) at low to moderate strains, albeit with lower moduli than predicted from the monomer chemical structure. At the high end of the strain ranges achieved, some of the networks exhibited strain hardening behavior. This work develops fundamental relationships between the molecular structure of the phenolic acids, including number and placement of functional groups, and the physical properties of the resulting networks.

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Section: Resultssupporting

confidence: 82%

Thiol–Ene Elastomers Derived from Biobased Phenolic Acids with Varying Functionality

et al. 2016

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“…Pyridine analog 17 was obtained via palladiumcatalyzed amination of pyridinyl bromide 4 with 3,5-Cl 2 PhNH 2 followed by base-mediated hydrolysis of the acetamide. 28 Finally, all biaryl-containing compounds (11, 35, 50, 91− 118) were prepared via Suzuki cross-coupling of the corresponding aryl chloride (7,13) or aryl bromide (32,38) analogs with arylboronic acids 29 or the corresponding MIDA boronates. 30 Discovery of Pyrimidineamines as T. brucei Ado-MetDC Inhibitors.…”

Section: ■ Resultsmentioning

confidence: 99%

“…Methylation of the linking amine (28) resulted in a sharp decrease in inhibitory activity in both enzyme and cell growth assays. The replacement of the amine with a thiol linker (29) eliminated enzyme inhibitory activity completely, presumably due to the effect on N1 acidity (pK a (N1) = 4.3).…”

Section: ■ Resultsmentioning

confidence: 99%

“…A primary amine is required at C2, and it is involved in an H-bond with the Glu266 carboxyl group. The amine linker could not be modified as there was a loss of potency when the linker was methylated (28), extended by one or two methylene links (30 and 31), or replaced with sulfur (29). The amine linker does not make any clear interactions with the protein, so its importance may relate to geometry and steric considerations.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

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Species-Selective Pyrimidineamine Inhibitors of Trypanosoma brucei S-Adenosylmethionine Decarboxylase

Volkov¹,

Brockway²,

Wring

et al. 2018

J. Med. Chem.

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New therapeutic options are needed for treatment of human African trypanosomiasis (HAT) caused by protozoan parasite Trypanosoma brucei. S-Adenosylmethionine decarboxylase (AdoMetDC) is an essential enzyme in the polyamine pathway of T. brucei. Previous attempts to target this enzyme were thwarted by the lack of brain penetration of the most advanced series. Herein, we describe a T. brucei AdoMetDC inhibitor series based on a pyrimidineamine pharmacophore that we identified by target-based high-throughput screening. The pyrimidineamines showed selectivity for T. brucei AdoMetDC over the human enzyme, inhibited parasite growth in whole-cell assay, and had good predicted blood-brain barrier penetration. The medicinal chemistry program elucidated structure-activity relationships within the series. Features of the series that were required for binding were revealed by determining the X-ray crystal structure of TbAdoMetDC bound to one analog. The pyrimidineamine series provides a novel starting point for an anti-HAT lead optimization.

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“…The Calcium 6 procedure was carried out via a previously published procedure with minor modifications using calcium 5 [ 48 , 49 , 50 ]. For this calcium accumulation assay, neuro-2a cells transiently expressing mouse α4β2 nAChRs were used (see above for transfection methods).…”

Section: Methodsmentioning

confidence: 99%

Novel Putative Positive Modulators of α4β2 nAChRs Potentiate Nicotine Reward-Related Behavior

et al. 2021

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The popular tobacco and e-cigarette chemical flavorant (−)-menthol acts as a nonselective, noncompetitive antagonist of nicotinic acetylcholine receptors (nAChRs), and contributes to multiple physiological effects that exacerbates nicotine addiction-related behavior. Menthol is classically known as a TRPM8 agonist; therefore, some have postulated that TRPM8 antagonists may be potential candidates for novel nicotine cessation pharmacotherapies. Here, we examine a novel class of TRPM8 antagonists for their ability to alter nicotine reward-related behavior in a mouse model of conditioned place preference. We found that these novel ligands enhanced nicotine reward-related behavior in a mouse model of conditioned place preference. To gain an understanding of the potential mechanism, we examined these ligands on mouse α4β2 nAChRs transiently transfected into neuroblastoma-2a cells. Using calcium flux assays, we determined that these ligands act as positive modulators (PMs) on α4β2 nAChRs. Due to α4β2 nAChRs’ important role in nicotine dependence, as well as various neurological disorders including Parkinson’s disease, the identification of these ligands as α4β2 nAChR PMs is an important finding, and they may serve as novel molecular tools for future nAChR-related investigations.

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Discovery of benzamide analogs as negative allosteric modulators of human neuronal nicotinic receptors: Pharmacophore modeling and structure–activity relationship studies

Cited by 7 publications

References 28 publications

Thiol–Ene Elastomers Derived from Biobased Phenolic Acids with Varying Functionality

Thiol–Ene Elastomers Derived from Biobased Phenolic Acids with Varying Functionality

Species-Selective Pyrimidineamine Inhibitors of Trypanosoma brucei S-Adenosylmethionine Decarboxylase

Novel Putative Positive Modulators of α4β2 nAChRs Potentiate Nicotine Reward-Related Behavior

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