NMDA Pharmacology

Question 1

What is the nature of NTD and LBD interaction and how was this shown by who?

Answer 1

NTD and LBD interact tightly via a large interface area

Crystal structures of intact heterotetrameric GluN1–GluN2B NMDA receptors complexed with agonists and allosteric inhibitors, ifenprodil or Ro 25-6981

Meyerson et al.,2014; Lee et al.,2014

Question 2

What confers proton sensitivity?

Answer 2

The fourth transmembrane region of LBD confers proton sensitivity that leads to a closed conformation of the bi-lobed GluN2B ATD architecture

Question 3

What is the mechanism of action of ifenprodil -who showed this?

Answer 3

Increases sensitivity to proton block

by binding to the NTD of the GluN2B subunit (Mott et al., 1998; Kew and Kemp, 2005)

Question 4

Nature of NTD binding ligands - and who showed this

Answer 4

Voltage-independent but activity-dependent and mediate an increase in glutamate potency (Kew et al., 1996; Mott et al., 1998)

Question 5

How does ketamine and MK-801 differ from NTD binding ligands? Who showed this?

Answer 5

Highly voltage-dependent blockers that show a trapping block mechanism with use-dependence of the block and high-affinity binding that may be an important factor in the side effects of these drugs (Kemp and McKernan, 2002

Question 6

What is the nature of Memantine block? and who showed this?

Answer 6

low-affinity channel block

faster unblocking rate

reduces use-dependence of the block

Lipton, 2006