NMDA Pharmacology 2

Question 1

What is an example of a non-selective NMDA antagonist?

Answer 1

AP-5

Question 2

What is an example of a GluN2B specific pharmacological agent?

Answer 2

Ifenprodil, a non-competitive negative allosteric modulator

Question 3

With what affinity does Ifenprodil bind GluN2B compared to other GluN2 subunits (and who)?

Answer 3

binds GluN2B subunit containing receptors with a more than 100-fold greater affinity over other GluN2 containing NMDARs (Williams, 1993)

Question 4

What is the significance of Ifenprodil selectivity for GluN2B?

Answer 4

allows it and other phenylethanolamine analogues to be used to study and characterise NMDAR subunits in native GluN2B containing neurons

Question 5

What part of ifenprodil binds and where does it bind to?

Answer 5

Karakas et al., (2011) found that the phenylethanolamine of Ifenprodil and analogues binds at the interface of GluN1 and GluN2B agonist binding domains.

Question 6

Have there been any GluN2A selective antagonists?

Answer 6

NVP-AAM077

Question 7

What was the problem with NVP-AAM077?

Answer 7

KB value was only five times greater for GluN2A than for GluN2B (Frizelle et al., 2006)

GluN2A deficient mice, where administration of NVP-AAM077 blocked 40% of NMDA generated current (Berberich et al., 2005)

Question 8

Who found what two selective GluN2A blockers in 2010?

Answer 8

Bettini et al., 2010

TCN201 and TCN213

Question 9

What are TCN201 and TCN213?

Answer 9

negative, non-competitive allosteric modulators of NMDARs containing GluN2A subunits and act to increase the rate of glycine dissociation from the GluN1 agonist-binding domain

Question 10

Why might the GluN1/GluN2 interface be a useful therapeutic target?

Answer 10

Mutations of residues present in the interface between GluN1 and GluN2A causes a change in the potency of TCN class of drugs (Hansen et al., 2012) implies that the interface could be a valuable target for new drugs for the modulation of NMDARs.

Question 11

What compound showed slightly higher selectivity for GluN2C/GluN2D containing receptors?

Answer 11

Costa et al., 2009 determined by Schild analysis that compounds such as UBP141, showed a slightly higher selectivity (5-10 times) for the GluN2C/GluN2D containing receptors than for other GluN2 subunits

Question 12

What was the problem with UBP141?

Answer 12

Selectivity not very high and would not be sufficient for clear subunit characterisation in native neurons, nor could it differentiate well between GluN2C/GluN2D

Question 13

What compound has higher selectivity for GluN2C/GluN2D containing receptors than UBP141?

Answer 13

QNZ46, a non-competitive antagonist that has a 50-fold greater selectivity for GluN2C/GluN2D than for other GluN2 subunits

Question 14

What was the problem with QNZ46?

Answer 14

It is glutamate-binding and thereby activity dependent (Hansen & Traynelis, 2011), which brings with it its own limitations.

Question 15

How does ketamine potency change depending on GluN2 subunit present?

Answer 15

when acting on receptors expressing GluN1/GluN2C subunits, has a three to four times greater potency than when acting on NMDARs containing other GluN2 subunits, but only in the presence of extracellular Mg2+ (Khlestova et al., 2016)

Question 16

How does ketamine’s anti-depressant effects dependon GluN2 subunit present?

Answer 16

mediated preferentially by GluN2B subunits, with deletion of GluN2B in vivo from principal cortical neurons imitating the anti-depressant action of Ketamine (Miller et al., 2014).