The role of the C-4 side chain of kainate and dihydrokainate in EAA receptor and transporter selectivity

Sonnenberg, Jennifer D.; Koch, H.; Willis, Colin L.; Bradbury, Faye A.; Dauenhauer, Danielle; Bridges, Richard J.; Chamberlin, A. Richard

doi:10.1016/s0960-894x(96)00284-3

Cited by 23 publications

(12 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is noteworthy that kainate is a selective blocker of EAAT2, whereas L-trans-pyrrolidine-2,4-dicarboxylic acid, which contains a more extended embedded glutamate-like conformation (21), is a general substrate (12). On the other hand, it has been shown that there is an inverse relationship between steric bulk at the 4-position and transport inhibition in the kainate-like derivatives: L-trans-2,3-homopyrrolidine-2,4-dicarboxylic acid, which has a hydrogen in that Blockers for the Bovine Glutamate/Aspartate Transporter 20338 position, is less active than kainate (isopropenyl group), itself less active than dihydrokainate (isopropyl group) (12,21,34). In this study, we demonstrated that even the THA derivatives possessing bulky groups could fit to the binding site of bovine EAAT1, possibly the result of the flexibility of the molecules.…”

Section: Discussionmentioning

confidence: 99%

New β-Hydroxyaspartate Derivatives Are Competitive Blockers for the Bovine Glutamate/Aspartate Transporter

Lebrun

Sakaitani²,

Shimamoto

et al. 1997

Journal of Biological Chemistry

View full text Add to dashboard Cite

Four subtypes of excitatory amino acid transporters (EAAT1-4) have been identified in the mammalian brain. A number of pharmacological agents have been developed to study their intrinsic properties and function. Up to now, blockers were available only for EAAT2, whereas all the inhibitors of glutamate uptake active on the other subtypes were proved to be substrates of the transporters. We synthesized five new derivatives of DLthreo-␤-hydroxyaspartic acid, a well known general substrate of EAATs, and investigated their potential blocking activity on the cloned bovine EAAT1 expressed in the Xenopus oocyte system, by using radiotracer and voltage-clamp techniques. Two of our derivatives proved to be substrates for bovine EAAT1, with reduced electrogenicity compared with their parent compound, and an affinity of 40 and 64 M. The last three derivatives displayed a blocking activity on bovine EAAT1. The affinity of DL-threo-␤-benzoyloxyaspartate and DLthreo-␤-(1-naphthoyl)oxyaspartate was determined by Schild analysis as 17.2 and 52.1 M, respectively. These blockers should help in the better understanding of the key intrinsic properties of EAAT1. Moreover, they appear as good candidates for a general blocking activity on EAATs.

show abstract

Section: Discussionmentioning

confidence: 99%

New β-Hydroxyaspartate Derivatives Are Competitive Blockers for the Bovine Glutamate/Aspartate Transporter

Lebrun

Sakaitani²,

Shimamoto

et al. 1997

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Kainate has a 2-carboxypyrrolidine-3-acetic acid backbone, and analogs containing this backbone, known as kainoids (Sonnenberg et al, 1996;Hodgson et al, 2005;Sagot et al, 2008;Bunch and Krogsgaard-Larsen, 2009), include domoic acid (Hampson et al, 1992;Alt et al, 2004) and acromelic acid (Kwak et al, 1992;Smith and McIlhinney, 1992). Agonist potency and efficacy are subunit-specific, because kainate and domoic acid are potent agonists of GluK1 and GluK2 but show low potency at GluK3 receptors (Table 6; Jane et al, 2009).…”

Section: Glutamate Receptor Ion Channelsmentioning

confidence: 99%

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

et al. 2010

View full text Add to dashboard Cite

“…In the instance of DZKA, the trifluoromethyldiazo group was chosen for several reasons. From a pharmacological perspective, modifications to the isopropenyl side chain are tolerated within the KA binding site, e.g., domoate and acromelate (Ishida and Shinozaki, 1991;Kwak et al, 1992;Chamberlin and Bridges, 1993;Sonnenberg et al, 1996), and the acyldiazo group exhibits greater similarities to the isopropenyl group than the other classic photoactivatible moieties, e.g., aryl azide. Inclusion of the trifluoromethyl group also increases the stability of acyldiazo compounds and decreases the rate of Wolff rearrangement that typically reduces the effectiveness of an activated acyldiazo in labeling studies.…”

Section: Discussionmentioning

confidence: 99%

“…Conversion of the isopropenyl group of KA into a trifluoromethyldiazoketone yielded a KA analogue that inhibited high-affinity [3H]KA binding with an IC 50 of 0.63 pM. Although this modification resulted in some loss of activity compared with KA (IC50 of 0.01 pM), it proved to be similar in potency to the respective analogue lacking a C4 side chain, i.e., 2carboxy-3-pyrrolidine acetate, and 1,500-fold more potent than dihydrokainate (Sonnenberg et al, 1996). Precedent that modifications to the C4 side chain are tolerated within the KA receptor binding site can also be found among other naturally occurring KA analogues.…”

Section: Discussionmentioning

confidence: 99%

Irreversible Inhibition of High‐Affinity [³H]Kainate Binding by a Novel Photoactivatable Analogue: (2′S,3′S,4′R)‐2′‐Carboxy‐4′‐(2‐Diazo‐1‐Oxo‐3,3,3‐Trifluoropropyl)‐3′‐Pyrrolidinyl Acetate

Willis

Wacker

Bartlett

et al. 1997

Journal of Neurochemistry

Self Cite

View full text Add to dashboard Cite

A photolabile trifluoromethyldiazoketone derivative of kainate (KA), (2 'S,3 'S,4'R)-2 '-carboxy-4 '-(2diazo-1 -oxo-3,3,3-trifluoropropyl)-3 '-pyrrolidinyl acetate (DZKA), was synthesized and evaluated as an irreversible inhibitor of the high-affinity KA site on rat forebrain synaptic plasma membranes (SPMs). In the absence of UV irradiation, DZKA preferentially blocked [ 3H]KA binding with an 1050 of 0.63 1iM, a concentration that produced little or no inhibition at AMPA or NMDA sites. At 100~sM, however, DZKA inhibited [ 3HI AMPA and L-[3H}glutamate binding by -50%. When examined electrophysiologically in HEK293 cells expressing human KA (GIuR6) or AMPA (GIuR1) subtypes, DZKA acted preferentially at KA receptors as a weak agonist. DZKA also exhibited little or no excitotoxic activity in mixed rat cortical cultures. Irreversible inhibition was assessed by pretreating SPMs with DZKA (50 1iM) in the presence of UV irradiation, removing unbound DZKA, and then assaying the reisolated SPMs for radioligand binding. This protocol produced a selective and irreversible loss of -50% of the [ 3H]KAsites. The binding was recoverable in SPMs pretreated with DZKA or UV alone. Coincubation with Lglutamate prevented the loss in [3H]KA binding, suggesting that the inactivation occurred at or near the ligand binding site. These results are consistent with the action of DZKA as a photoaffinity ligand for the KA site and identify the analogue as a valuable probe for future investigations of receptor structure and function. Key Words: Excitatory amino acids-Kainate receptor-Photoaffinity ligand. J. Neurochem. 68, 1503Neurochem. 68, -1510Neurochem. 68, (1997.L-Glutamate participates in several activities within the CNS, including fast synaptic signaling, long-term potentiation, development, synaptic plasticity, and neuronal pathology (for review, see Cotman et al., 1995), through the activation of various excitatory amino acid (EAA) receptors. These receptors have been functionally divided between those that gate ion channels (ionotropic) and those linked to second messenger systems (metabotropic), such as the cyclic AMP or inositol phosphate/diacylglycerol pathways (Collingridge and Watkins, 1994;Nakanishi and Masu, 1994;Schoepp, 1994;Cotman et al., 1995). Tonotropic receptors are further subdivided into Nmethyl-D-aspartate (NMDA), kainate (KA), and aamino -3 -hydroxy -5 -methyl -4 -isoxazole propionate (AMPA) classes based on agonist selectivity.

show abstract

The role of the C-4 side chain of kainate and dihydrokainate in EAA receptor and transporter selectivity

Cited by 23 publications

References 11 publications

New β-Hydroxyaspartate Derivatives Are Competitive Blockers for the Bovine Glutamate/Aspartate Transporter

New β-Hydroxyaspartate Derivatives Are Competitive Blockers for the Bovine Glutamate/Aspartate Transporter

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

Irreversible Inhibition of High‐Affinity [³H]Kainate Binding by a Novel Photoactivatable Analogue: (2′S,3′S,4′R)‐2′‐Carboxy‐4′‐(2‐Diazo‐1‐Oxo‐3,3,3‐Trifluoropropyl)‐3′‐Pyrrolidinyl Acetate

Contact Info

Product

Resources

About

The role of the C-4 side chain of kainate and dihydrokainate in EAA receptor and transporter selectivity

Cited by 23 publications

References 11 publications

New β-Hydroxyaspartate Derivatives Are Competitive Blockers for the Bovine Glutamate/Aspartate Transporter

New β-Hydroxyaspartate Derivatives Are Competitive Blockers for the Bovine Glutamate/Aspartate Transporter

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

Irreversible Inhibition of High‐Affinity [3H]Kainate Binding by a Novel Photoactivatable Analogue: (2′S,3′S,4′R)‐2′‐Carboxy‐4′‐(2‐Diazo‐1‐Oxo‐3,3,3‐Trifluoropropyl)‐3′‐Pyrrolidinyl Acetate

Contact Info

Product

Resources

About

Irreversible Inhibition of High‐Affinity [³H]Kainate Binding by a Novel Photoactivatable Analogue: (2′S,3′S,4′R)‐2′‐Carboxy‐4′‐(2‐Diazo‐1‐Oxo‐3,3,3‐Trifluoropropyl)‐3′‐Pyrrolidinyl Acetate