AMPA and Kainate receptors are built from closely related subunits (AMPA - GluR1-4; Kainate - GluR5-7, KA-1,2). The diagnostic agonists for these two receptors (AMPA and kainate, respectively) also activate the other receptor (see below). The synthesis of compounds that can discriminate bwetween these closely related receptors has thus proved a great challenge to medicinal chemists. A further challenge has been to develop pharmacological agent that can discriminate between AMPA or kainate receptor that contain particular subunits. The information detailed below has been obtained by expressing the human isoforms of the receptor subunits to create homomeric channels. Many of the compounds described are available through Tocris Cookson. Click on the link for details of compounbds that act on NMDA and mGlu receptors Compounds named in Red are as yet commercially unavailable; click on the y symbol to follow a PubMed link.
AMPA Receptor Agonists
As would be expected, AMPA itself shows a good selectivity for AMPA receptors over kainate receptors (10-20 fold higher affinity for GluR1-4 over a representative kainate subunit, GluR5). However, it shows no selectivity for different AMPA receptor subunits. In contrast, compounds based on willardine are not only more selective for AMPA receptors than AMPA itself (5-fluorowillardiine has a 70-150 fold higher affinity for GluR1,2 over GluR5), but also shows selectivity for AMPA receptor subunits. 5-fluorowillardiine shows a 10-20 fold selectivity for GluR1 and 2 over GluR4, while 5-chloro-6-azawillardiine shows some selectivity for GluR4 over GluR1 and 2, but at the cost of losing selectivity for AMPA over kainate receptors. 5-iodo-6-azawillardiine shows a similar pattern of selectivity (see below).
Ki Values (nM) for Displacement of [ 3 H]-AMPA Binding
hGluR1
103 ± 13
14.7 ± 1.3
7.1 6 ± 2.2
hGluR2
107 ± 16
25.1 ± 5.2
16.7 ± 6.6
hGluR4
155 ± 10
305 ± 107
3.6 ± 1.4
Ki Values (nM) for Displacement of [ 3 H]-Kainate Binding
hGluR5
2144 ± 416
1820 ± 149
30.9 ± 5.4
(5-Cl-6-azawillardine is available from Dr David Jane.)
Kainate Receptor Agonists
A number of agonists show selectivity for kainate receptors over AMPA receptors. Apart from kainate itself, ATPA and 5-iodowillardiine show high degrees of selectivity for GluR5 over AMPA receptor subunits (1400 and 700 fold, respectively). Neither ATPA or 5-iodowillardiine significantly activate GluR6; however, both have been shown to have weak agonist activity at GluR6/KA2 heteromers. 5-iodowillardiine also has weak agonist activity at GluR7/KA2 heteromeric receptors. Interestingly, 5-iodowillardiine also shows a degree of selectivity for GluR1 and 2 over GluR4, whereras this is reversed for 5-iodo-6-azawillardiine (compare this with 5-Cl-6-azawill). This compound also shows a similar affinity for GluR5. Thus far there are no selective agonists for any other kainate receptor subunits.
