Pyridyl amides as potent inhibitors of T-type calcium channels

Reger, Thomas S.; Yang, Zhi; Schlegel, K.; Shu, Youheng; Mattern, Christa; Cube, Rowena V.; Rittle, Kenneth E.; McGaughey, Georgia B.; Hartman, George D.; Tang, Cuyue; Ballard, Jeanine; Kuo, Yuhsin; Prueksaritanont, Thomayant; Nuss, Cindy E.; Doran, Scott M.; Fox, Steven V.; Garson, Susan L.; Li, Yuxing; Kraus, Richard L.; Uebele, Victor N.; Renger, John J.; Barrow, James C.

doi:10.1016/j.bmcl.2011.01.089

Cited by 28 publications

(22 citation statements)

References 42 publications

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“…Recently, TTA-A2, a potent and specific synthetic inhibitor of T-current, was described (Uebele et al, 2009a,b;Kraus et al, 2010;Reger et al, 2011). As observed with endogenous lipids, TTA-A2 inhibited the Ca v 3 current at physiologic HP but not at very negative potentials (i.e., 2110 mV) (Kraus et al, 2010;Francois et al, 2013).…”

Section: Resultsmentioning

confidence: 94%

“…In addition, TTA-A2 affects sleep/wake patterns (Uebele et al, 2009a;Kraus et al, 2010;Reger et al, 2011) and displays antipsychotic properties (Uslaner et al, 2012). Similarly, bioactive lipids inhibiting Tcurrents have been implicated in several functions, including pain perception (Bradshaw and Walker, 2005;Burstein, 2008;Basbaum et al, 2009), sleep, and epilepsy (Chen and Bazan, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…Various synthetic T-channel blockers have been described in the past few years (McGivern, 2006;Lory and Chemin, 2007;Giordanetto et al, 2011), including TTA-A2 [(R)-2-(4-cyclopropylphenyl)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)acetamide], a potent and specific inhibitor of T-current (Uebele et al, 2009a,b;Kraus et al, 2010;Reger et al, 2011). In vivo studies have demonstrated that TTA-A2 reduces absence epilepsy seizures (Uebele et al, 2009b;Reger et al, 2011), pain perception (Francois et al, 2013), nicotine selfadministration (Uslaner et al, 2010), and weight gain (Uebele et al, 2009a), and it ameliorates the sleep quality (Uebele et al, 2009a;Kraus et al, 2010;Reger et al, 2011) and displays antipsychotic properties (Uslaner et al, 2012).…”

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confidence: 99%

“…In vivo studies have demonstrated that TTA-A2 reduces absence epilepsy seizures (Uebele et al, 2009b;Reger et al, 2011), pain perception (Francois et al, 2013), nicotine selfadministration (Uslaner et al, 2010), and weight gain (Uebele et al, 2009a), and it ameliorates the sleep quality (Uebele et al, 2009a;Kraus et al, 2010;Reger et al, 2011) and displays antipsychotic properties (Uslaner et al, 2012).…”

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confidence: 99%

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Cross-Modulation and Molecular Interaction at the Cav3.3 Protein between the Endogenous Lipids and the T-Type Calcium Channel Antagonist TTA-A2.

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Nuss

Bidaud

et al. 2014

Molecular Pharmacology

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Section: Resultsmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Cross-Modulation and Molecular Interaction at the Cav3.3 Protein between the Endogenous Lipids and the T-Type Calcium Channel Antagonist TTA-A2.

Cazade

Nuss

Bidaud

et al. 2014

Molecular Pharmacology

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“…Cells were held at membrane potentials that deinactivate (−110 mV) or half inactivate Ca V 3 (−80 mV) and then depolarized to −50 mV to activate Ca V 3. AIS Ca transients evoked from −110 mV were reduced to 18 ± 6% of baseline by the Ca V 3 selective antagonist TTA-P2 (2 μM, Reger et al, 2011). As observed previously, quinpirole did not alter whole-cell currents at either voltage (norm.…”

Section: Resultsmentioning

confidence: 99%

β-Arrestin-Dependent Dopaminergic Regulation of Calcium Channel Activity in the Axon Initial Segment

et al. 2016

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G-protein coupled receptors (GPCRs) initiate a variety of signaling cascades depending on effector coupling. β-arrestins, which were initially characterized by their ability to “arrest” GPCR signaling by uncoupling receptor and G protein, have recently emerged as important signaling effectors for GPCRs. β-arrestins engage signaling pathways that are distinct from those mediated by G-protein. As such, arrestin-dependent signaling can play a unique role in regulating cell function, but whether neuromodulatory GPCRs utilize β-arrestin-dependent signaling to regulate neuronal excitability remains unclear. Here, we find that D3 dopamine receptors (D3R) regulate axon initial segment (AIS) excitability through β-arrestin-dependent signaling, modifying CaV3 voltage dependence to suppress high frequency action potential generation. This non-canonical D3R signaling thereby gates AIS excitability via pathways distinct from classical GPCR signaling pathways.

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Addition of Non‐Stabilized Carbon‐Based Nucleophilic Reagents to Chiral N ‐Sulfinyl Imines

et al. 2019

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Natural products and pharmaceuticals that contain chiral branched amines are compounds of considerable interest. One strategy for preparing chiral branched amines involves the addition of a nucleophile to an imine bearing a readily cleavable chiral auxiliary. Sulfinamide‐based auxiliaries are well‐suited to this approach because (i) many sulfonamides are commercially available or can be prepared by efficient synthetic methods, (ii) N ‐sulfinyl aldimines and ketimines can be prepared in a straightforward manner, (iii) the chiral amine products are obtained with high diastereomeric ratios across a wide range of carbon‐based nucleophiles, and (iv) the N ‐sulfinyl group is cleaved under mild conditions. This chapter focuses on the addition of non‐stabilized, carbon‐based nucleophiles to N ‐sulfinyl aldimines and ketimines. Specifically, additions of alkyl, alkenyl, aryl, allylic, propargylic, alkynyl, and cyano nucleophiles are presented. Factors that can influence the stereoselectivity of the addition reaction are presented, along with the most prevalent reaction conditions employed for each class of nucleophile. Nucleophilic additions to N ‐sulfinyl aldimines and ketimines are key steps in the syntheses of a number of drug discovery targets and natural products, examples of which are highlighted in this review.

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Pyridyl amides as potent inhibitors of T-type calcium channels

Cited by 28 publications

References 42 publications

Cross-Modulation and Molecular Interaction at the Cav3.3 Protein between the Endogenous Lipids and the T-Type Calcium Channel Antagonist TTA-A2.

Cross-Modulation and Molecular Interaction at the Cav3.3 Protein between the Endogenous Lipids and the T-Type Calcium Channel Antagonist TTA-A2.

β-Arrestin-Dependent Dopaminergic Regulation of Calcium Channel Activity in the Axon Initial Segment

Addition of Non‐Stabilized Carbon‐Based Nucleophilic Reagents to Chiral N ‐Sulfinyl Imines

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