Kainate Receptor Antagonists: Recent Advances and Therapeutic Perspective
Abstract
:1. Introduction
2. Structure and Properties of Kainate Receptors
2.1. Structure of Ionotropic Kainate Receptors
2.2. Activity of Kainate Receptors
2.3. Pathophysiological Role of Kainate Receptors
3. Competitive Antagonists of the Kainate Receptors
3.1. Quinoxaline-2,3-diones
cmpd | Native iGluRs | ||
---|---|---|---|
AMPA [3H]AMPA | KA [3H]KA | NMDA [3H]CPP or [3H]Glu | |
CNQX (1) | 0.30 ± 0.15 (IC50) a 0.25 ± 0.01 (Ki) b | 1.5 ± 0.3 (IC50) a 2.7 ± 0.1 (IC50) b | 25 (IC50) a 45 ± 4 (IC50) b |
DNQX (2) | 0.50 ± 0.10 (IC50) a | 2.0 ± 0.1 (IC50) a | 40 (IC50) a |
NBQX (3) | 0.046 ± 0.001 (Ki) b 0.15 ± 0.01 (IC50) c 0.12 ± 0.04 (Ki) d | 6.8 ± 0.2 (IC50) b 4.8 ± 0.5 (IC50) c 3.7 ± 1.0 (Ki) d | >100 (IC50) b >90 (IC50) c |
YM90K (4) | 0.071 ± 0.002 (Ki) b | 4.4 ± 0.1 (IC50) b | >100 (IC50) b |
YM872 (5) | 0.096 ± 0.002 (Ki) b | 4.6 ± 0.1 (IC50) b | >100 (IC50) b |
ZK200775 (6) | 0.12 ± 0.09 (IC50) e | 2.5 ± 0.2 (IC50) e | 2.8 ± 0.35 (IC50) e |
cmpd | Ki [μM] | ||||
---|---|---|---|---|---|
Recombinant Homomeric iGluRs | |||||
GluK1 | GluK2 | GluK3 | GluK5 | GluA2 | |
CNQX (1) | 1.3 ± 0.3 a | 1.1 ± 0.1 b 1.5 ± 0.01 a | 0.64 ± 0.05 a | 8.4 ± 0.9 c,d | 0.33 ± 0.03 a |
DNQX (2) | 0.65 ± 0.03 a | 2.1 ± 0.3 a | 0.36 ± 0.03 a | 7.1 ± 0.9 a | 0.25 ± 0.01 a |
NBQX (3) | 1.4 ± 0.4 e 12 ± 4 f 2.6 ± 0.1 d | 2.3 e 13 ± 2 f 5.4 ± 1.2 d | 3.2 e 24 ± 7 f 18 ± 8 b 3.4 ± 0.6 d | 19 ± 8 e >100 f >100 c 152 ± 23 d | 0.26 ± 0.04 f 0.077 ± 0.010 d |
LU97175 (7) | 0.088 ± 0.033 e 0.70 ± 0.12 d | 0.31 ± 0.19 e 0.49 ± 0.06 d | 0.022 ± 0.003 e 0.19 ± 0.029 d | 6.9 ± 0.03 e 24 ± 4 d | 1.52 ± 0.25 d |
8g | 0.0038 | 4.1 | 0.68 | 20 | nd |
9g | 0.012 | 1.4 | 1.4 | 25 | nd |
10g | 0.43 | 23 | nd | >30 | nd |
11d | 1.1 ± 0.1 | 2.0 ± 0.1 | 0.53 ± 0.15 | 43 ± 11 | 4.9 ± 0.6 |
12d | 0.80 ± 0.11 | 0.81 ± 0.08 | 0.28 ± 0.03 | 31 ± 4 | 6.2 ± 1.4 |
13d | 1.1 ± 0.1 | 0.91 ± 0.17 | 0.14 ± 0.02 | 26 ± 2 | 4.1 ± 0.6 |
14d | 0.80 ± 0.18 | 0.84 ± 0.19 | 0.33 ± 0.01 | 45 ± 4 | 6.0 ± 0.1 |
15h | 0.17 ± 0.01 | 0.52 ± 0.14 | 0.08 ± 0.01 | 5.2 ± 0.30 | 5.7 ± 0.3 |
16d | >100 | ≈100 | 2.9 ± 0.3 | >100 | 24 ± 6 |
17i | ≈100 | >100 | 0.25 ± 0.01 | >100 | >100 |
18i | 0.15 ± 0.05 | 0.091 ± 0.01 | 0.13 ± 0.03 | 3.8 ± 0.1 | 0.23 ± 0.02 |
19a | 16 ± 1 | 9.5 ± 1.2 | 59 ± 3 | nd | 21 ± 2 |
20j | 1.2 ± 0.7 | 33 ± 3 | 37 ± 4 | nd | >100 |
3.2. α-Amino Acid Antagonists
3.2.1. Willardiines
cmpd | Native iGluRs | |
---|---|---|
AMPA IC50 a | GluK1-Containing KARs KD b | |
UPB282 (21) | 10 ± 2 c | 9.3 ± 0.5 d |
UBP296 (22) | 98 ± 9 d | 1.1 ± 0.1 d |
UBP302 (23) | 106 ± 13 d | 0.40 ± 0.05 d |
UBP310 (24) | 16 ± 5 e | 0.018 ± 0.004 e |
ACET (UBP316, 25) | 17 ± 1 e | 0.012 ± 0.001 e |
cmpd | Recombinant Homomeric iGluRs | ||||
---|---|---|---|---|---|
GluK1 | GluK2 | GluK3 | GluK5 | GluA2 | |
UPB282 (21) a | nd | >100 (IC50) | nd | >1000 (IC50) | nd |
UBP296 (22) | 0.60 ± 0.10 (Kb) b | >1000 (IC50) a | 374 ± 122 (Ki) c | >100 (IC50) a | >300 (Kb) b |
UBP302 (23) | 0.60 ± 0.10 (Kb) d | >1000 (Ki) c >300 (IC50) d | 4.0 ± 0.2 (IC50) e | nd | >300 (IC50) d |
UBP310 (24) | 0.022 ± 0.005 (Ki) f 0.010 ± 0.001 (Kb) d | >100 (IC50) d | 0.93 ± 0.12 (Ki) f 0.023 ± 0.002 (IC50) e | >100 (Ki) g | >100 (IC50) d |
ACET (25) | 0.0070 ± 0.0010 (Kb) d | >100(IC50) d | 0.092 ± 0.009 (IC50) e | nd | >100 (IC50) d |
3.2.2. Decahydroisoquinolines
cmpd | Ki [μM] | |||
---|---|---|---|---|
Recombinant Homomeric iGluRs | ||||
GluA2 | GluK1 | GluK3 | GluK5 | |
LY293558 (26) a | 3.2 ± 0.3 | 4.2 ± 0.3 | >100 | >100 |
LY377770 (27) b | 35 ± 6 | 3.1 ± 1.0 | nd | nd |
LY382884 (28) c | 553 | 3.6 | nd | nd |
29d | 117 ± 16 | 0.16 ± 0.08 | 49 ± 2 | nd |
LY466195 (31) e | 269 ± 22 | 0.050 ± 0.020 | 8.9 ± 0.2 | 270 ± 31 |
LY458545 (32) f | 8.3 ± 2.0 | 1.7 ± 0.4 | nd | nd |
LY457694 (33) f | 5.5 ± 1.8 | 1.6 ± 0.6 | nd | nd |
LY545694 (34) g | 30 | 0.2 | nd | nd |
3.2.3. Other α-Amino Acid Antagonists
cmpd | IC50/Ki [μM] | Ki [μM] | ||||
---|---|---|---|---|---|---|
Native iGluRs | Recombinant Homomeric iGluRs | |||||
AMPA [3H]AMPA | KA [3H]KA | GluK1 | GluK2 | GluK3 | GluA2 | |
35 | 16 ± 1 (IC50) a | >100 (IC50) a | 2.2 ± 0.5 b 2.9 ± 0.3 c 2.6 ± 0.4 d | >100 c,d | >100 c >1000 d | 60 ± 5 d |
36e | 3.4 ± 0.3 (IC50) | nd | 3.0 ± 0.8 | nd | 14 ± 3 | nd |
(S)-36 e | nd | nd | 1.5 ± 0.2 | nd | 8.0 ± 1.1 | nd |
37c | >100 (IC50) | >100 (IC50) | 2.8 ± 0.8 | >100 | >100 | nd |
38 | 4.6 ± 0.2 (IC50) c | >100 (IC50) c | 92 ± 2 f | 78 ± 10 f | 52 ± 3 f | 5.0 ± 0.4 f |
39g | 51 ± 10 (IC50) | 22 ± 2 (IC50) | 4.3 ± 0.4 | >100 | 8.1 ± 0.6 | 67 ± 16 |
40d | 2.0 (IC50) | 1.4 (IC50) | 4.8 ± 1.5 | 10–100 | 0.87 ± 0.09 | nd |
41d | 48 (IC50) | 22 (IC50) | 0.62 ± 0.10 | 81 ± 8 | 2.2 ± 0.4 | nd |
42h | >100 (Ki) | >100 (Ki) | 4.0 | >100 | >100 | nd |
43 | nd | nd | 0.13 ± 0.02 i | >100 i | >100 i | >100 j |
44 | nd | nd | 2.4 j 0.56 k | 7.7 j 6.7 k | >100 k | >100 j >30 k |
45l | nd | nd | 0.16 ± 0.02 | 99 ± 22 | 7.5 ± 0.3 | 73 ± 15 |
46m | >100 (Ki) | >100 (Ki) | 177 ± 4 | >5000 | 6.4 ± 0.7 | >1000 |
3.3. Structurally Dissimilar AMPAR/KAR Antagonists
4. Non-Competitive Antagonists and Channel Blockers of Kainate Receptors
5. RNA Aptamers
6. The Therapeutic Potential of Non-NMDA Receptors Antagonists
Disease | Target/Mechanism | Drug | Stage of Development |
---|---|---|---|
Neuropathic Pain | Competitive GluK1 antagonist | LY 5,454,694 tosylate | Phase II (compl. 2010) |
Competitive AMPAR/GluK1 antagonist | NGX426 (tezampanel prodrug) | Phase I (compl. 2008) | |
Competitive AMPAR/KA antagonist | NS 1209 | Phase II (compl. 2007) | |
Competitive AMPAR/GluK1 antagonist | Tezampanel (NGX424 LY 293558) | Phase I | |
Migraine | Competitive AMPAR/GluK1 antagonist | Tezampanel | Phase II (compl. 2009) |
Competitive AMPAR antagonist | Selurampanel | Phase II (compl. 2012) | |
Non-competitive KAR antagonist | Topiramate | Phase IV (compl. 2015) | |
Epilepsy | Competitive AMPAR antagonist | Becampanel | Phase II (compl. 2011) |
Competitive AMPAR antagonist | Selurampanel | Phase II (compl. 2012) | |
Competitive AMPAR antagonist | NS 1209 | Phase II | |
Non-competitive KAR antagonist | Topiramate | Phase IV (compl. 2010) | |
Non-competitive AMPAR/KAR antagonist | Perampanel | Marketed 2012 | |
Non-competitive AMPAR antagonist | Talampanel | Phase II (compl. 2006) | |
Stroke and Head Trauma | Competitive AMPAR antagonist | ZK200775 | Phase II (dis) |
Amyotrophic Lateral Sclerosis | Non-competitive AMPAR antagonist | Talampanel | Phase II (compl. 2010) |
Non-competitive AMPAR/KAR antagonist | Perampanel | Phase II (terminated 2021) | |
Parkinson’s Disease | Non-competitive AMPAR antagonist | Talampanel | Phase II (compl. 2006) |
Non- competitive AMPAR/KAR antagonist | Perampanel | Phase III (compl. 2012) | |
Eating Disorder | Non-competitive KAR antagonist | Topiramate | Phase I (compl. 2018) |
Obesity | Non-competitive KAR antagonist | Topiramate | Phase II (compl. 2017) |
Chronic Subjective Tinnitus | Competitive AMPAR antagonist | Selurampanel | Phase II (compl. 2012) |
Tourette Syndrome | Non-competitive KAR antagonist | Topiramate | Phase III (compl. 2008) |
Glial Brain Tumors | Non-competitive AMPAR/KAR antagonist | Perampanel | Phase IV (compl. 2017) |
Non-competitive AMPAR antagonist | Talampanel | Phase II (compl. 2011) | |
Alcohol Dependence | Non-competitive KAR antagonist | Topiramate | Phase III (compl. 2011) |
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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cmpd | Native iGluRs | Recombinant Homomeric iGluRs | |||
---|---|---|---|---|---|
AMPA | KA | GluA2 | GluK1 | GluK3 | |
47a | 16 (Ki) | 0.62 (IC50) | nd | nd | nd |
48, selurampanel b | 0.19 (IC50) | >100 (IC50) | nd | nd | nd |
49, NS 1209 c | 0.043 (IC50) c | 81 (IC50) c | 0.030 (Ki) d | 0.74 (Ki) d | nd |
50, RPR117824 e | 0.018 (IC50) | nd | nd | nd | nd |
cmpd | IC50 [μM] | |||
---|---|---|---|---|
Recombinant Homomeric iGluRs | ||||
GluA1 | GluA2 | GluK1 | GluK2 | |
51, GYKI 53655 | 5.9 ± 0.1 a | 1.9 ± 0.8 b | >100 b | 198 ± 53 b |
53, NS 3763 c | nd | nd | 1.6 ± 0.2 | >30 |
54d | nd | nd | 4.0 | 0.7 |
Receptor | IC50 [μM] |
---|---|
GluA4 | 0.56 ± 0.12 |
GluK1 | 19 ± 5 |
GluK2 | 26 ± 10 |
GluK3 | 41 ± 6 |
GluK1/5 | 2.8 ± 0.3 |
GluK2/5 | 0.85 ± 0.09 |
GluK3/5 | 14 ± 8 |
GluK1/NETO1 | 11 ± 4 |
GluK1/NETO2 | 19 ± 4 |
GluK2/NETO1 | 5.4 ± 0.9 |
GluK2/NETO2 | 5.8 ± 1.0 |
GluK1/5/NETO2 | 0.99 ± 0.15 |
GluK2/5/NETO1 | 0.69 ± 0.16 |
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Chałupnik, P.; Szymańska, E. Kainate Receptor Antagonists: Recent Advances and Therapeutic Perspective. Int. J. Mol. Sci. 2023, 24, 1908. https://doi.org/10.3390/ijms24031908
Chałupnik P, Szymańska E. Kainate Receptor Antagonists: Recent Advances and Therapeutic Perspective. International Journal of Molecular Sciences. 2023; 24(3):1908. https://doi.org/10.3390/ijms24031908
Chicago/Turabian StyleChałupnik, Paulina, and Ewa Szymańska. 2023. "Kainate Receptor Antagonists: Recent Advances and Therapeutic Perspective" International Journal of Molecular Sciences 24, no. 3: 1908. https://doi.org/10.3390/ijms24031908