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Review
. 2019 Feb 15:164:471-498.
doi: 10.1016/j.ejmech.2018.12.054. Epub 2018 Dec 28.

Investigation of the structural requirements for N-methyl-D-aspartate receptor positive and negative allosteric modulators based on 2-naphthoic acid

Mark W Irvine  1 , Guangyu Fang  1 , Kiran Sapkota  2 , Erica S Burnell  3 , Arturas Volianskis  4 , Blaise M Costa  5 , Georgia Culley  1 , Graham L Collingridge  6 , Daniel T Monaghan  2 , David E Jane  7
Affiliations
Review

Investigation of the structural requirements for N-methyl-D-aspartate receptor positive and negative allosteric modulators based on 2-naphthoic acid

Mark W Irvine et al. Eur J Med Chem. .

Abstract

The N-methyl-D-aspartate receptor (NMDAR), a ligand-gated ion channel activated by L-glutamate and glycine, plays a major role in the synaptic plasticity underlying learning and memory. NMDARs are involved in neurodegenerative disorders such as Alzheimer's and Parkinson's disease and NMDAR hypofunction is implicated in schizophrenia. Herein we describe structure-activity relationship (SAR) studies on 2-naphthoic acid derivatives to investigate structural requirements for positive and negative allosteric modulation of NMDARs. These studies identified compounds such as UBP684 (14b), which act as pan potentiators by enhancing NMDAR currents in diheteromeric NMDAR tetramers containing GluN1 and GluN2A-D subunits. 14b and derivatives thereof are useful tools to study synaptic function and have potential as leads for the development of drugs to treat schizophrenia and disorders that lead to a loss of cognitive function. In addition, SAR studies have identified a series of styryl substituted compounds with partial NAM activity and a preference for inhibition of GluN2D versus the other GluN2 subunits. In particular, the 3-and 2-nitrostyryl derivatives UBP783 (79i) and UBP792 (79h) had IC50s of 1.4 μM and 2.9 μM, respectively, for inhibition of GluN2D but showed only 70-80% maximal inhibition. GluN2D has been shown to play a role in excessive pain transmission due to nerve injury and potentially in neurodegenerative disorders. Partial GluN2D inhibitors may be leads for the development of drugs to treat these disorders without the adverse effects observed with full NMDAR antagonists.

Keywords: 2-Naphthoic acid; GluN2; N-Methyl-D-aspartate receptor; NMDA; Negative allosteric modulator; Positive allosteric modulator.

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Figures

Figure 1
Figure 1
Structures of known NMDAR positive and negative allosteric modulators.
Figure 2
Figure 2
Potentiation of NMDAR responses by 2-naphthoic acid derivatives. Select PAMs identified in Table 1 were tested for activity at various concentrations to determine potency and efficacy. Compounds were tested on NMDA receptors containing GluN1a and the indicated GluN2 subunit expressed in Xenopus oocytes. After obtaining a steady state NMDAR response evoked by 10 μM L-glutamate and 10 μM glycine, test compounds were co-applied with agonists at various concentrations. Values (mean ± s.e.m.) represent the % potentiation of the response above the agonist-alone response.
Figure 3
Figure 3
Inhibition of NMDAR responses by 2-naphthoic acid derivatives. A. 7, B. 79h, C. 79i, D. 79j. NAMs described in Table 6 were tested for activity at various concentrations to determine inhibitory potency and the percentage of maximum inhibition. Compounds were tested on NMDA receptors containing GluN1a and the indicated GluN2 subunit expressed in Xenopus oocytes. After obtaining a steady state NMDAR response evoked by 10 μM L-glutamate and 10 μM glycine, test compounds were co-applied with agonists at various concentrations. Values (mean ± s.e.m.) represent the % response in the presence of the test compound compared to response in the presence of agonists alone.
Figure 4
Figure 4
79h does not compete with L-glutamate or glycine at NMDARs. 30 μM 79h did not display reduced inhibition of GluN1/GluN2C (blue) and GluN1/GluN2D (gray) NMDAR responses evoked by high concentrations of agonists (300 μM glutamate / 300 μM glycine; dark blue/gray) than by low agonist concentrations (10 μM glutamate / 10 μM glycine; light blue/gray).
Scheme 1<sup>a</sup>
Scheme 1a
aReagents and conditions: (a) Alkene, P(o-tolyl)3, TEA, Pd(OAc)2, DMF, 100 °C, 18 h; (b) H2, 10% Pd/C, rt, 18 h; (c) (i) LiOH or NaOH (aq), THF, 65 °C or dioxane, 80 °C, (ii) 1 M HCI (aq); (d) (n-Bu)3SnCH=CH2, Pd(PPh3)4, toluene, reflux, 4 h; (e) CH2I2, Et2Zn, DCM, 0 °C, 18 h; (f) (i) NaOH (aq), THF/H20, rt, 18 h, (ii) 1 M HCI (aq).
Scheme 2<sup>a</sup>
Scheme 2a
aReagents and conditions: (a) LiAIH4, THF, 0 °C then 65 °C, 4 h; (b) PBr3, 0 °C then rt, 1 h; (c) NaCN, TBAB, H20/DCM (1:1), rt, 48 h; (d) H2S04, Ac0H/H20 (1:1), 118 °C, 18 h; (e) Br2, AcOH, 50 °C; (f) (i) 1-Bromobutane, NaOH, Et0H/H20 (3:1), 78 °C, 18 h, (ii) 10% NaOH, 78 °C, 2 h, (iii) 2 M HCI (aq).
Scheme 3<sup>a</sup>
Scheme 3a
aReagents and conditions: (a) Alkene, P(o-tolyl)3, TEA, Pd(OAc)2, DMF, 100 °C, 18 h; (b) H2,10% Pd/C, rt, 18 h; (c) (i) NaOH, THF/H20, 65 °C, (ii) 1 M HCI (aq); (d) 4-methylpent-1-yne, NHEt2, Cui, Pd(Ph3)2CI2, THF, 50 °C, 18 h; (e) (i) LiOH, dioxane/HzO, rt, 18 h, (ii) 1 M HCI (aq); (f) (i) NaOH, dioxane/HzO, rt, 18 h, (ii) 1 M HCI (aq).
Scheme 4<sup>a</sup>
Scheme 4a
aReagents and conditions: (a) Isobutanol, H2S04, reflux, 18 h; (b) CO, DPPP, NEt3, Pd(OAc)2, H2O/DMF, 85 °C, 24 h; (c) (i) ethyl 4-methylvalerate, LiHMDS, THF, −78 °C then rt 3 h, (ii) 1 M NaOH (aq), 50 °C, 18 h, (iii) conc HCI (aq), 60 °C, 1 h; (d) CO, DPPP, NEt3, Pd(OAc)2, MeOH/DMF, 90 °C, 18 h; (e) (i) LiOH, dioxane/H20, rt, 18 h, (ii) 1 M HCI (aq); (f) 4-pentyn-2-ol, NEt3, CuBr, Pd(PPh3)4, 65 °C, 18 h; (g) H2, 10% Pd/C, EtOH, rt, 1 h; (h) DMP, DCM, rt, 2 h; (i) methyl diethylphosphonoacetate, KHMDS, THF, 0 °C 1 h then rt 4 h; Q) H2, 10% Pd/C, EtOH, rt, 1 h; (k) CH3PPh3Br, KHMDS, THF, −78 °C 1 h then rt 2 h.
Scheme 5<sup>a</sup>
Scheme 5a
aReagents and conditions: (a) 2-Methyipropan-1-thiol, Na, EtOH; (b) (i) LiOH, dioxane/H2O, rt, 18 h, (ii) 1 M HCI (aq); (c) Isobutylamine, NEt3, DCM, 0 °C then rt, 18 h; (d) Isobutyryl chloride, NEt3, DCM, 0 °C then rt, 1 h, (ii) 2 M NaHC03 (aq), 0 °C, 3 h, (iii) 1 M HCI (aq).
Scheme 6<sup>a</sup>
Scheme 6a
aReagents and conditions: (a) 2-Methylpropan-1-ol, Na, DMF, rt, 7 h; (b) CO, DPPP, NEt3, Pd(OAc)2, H2O/DMF, 85 °C, 24 h; (c) ethyl 4-methylvalerate, KHMDS, THF, −78 °C 0.5 h then rt, 18 h; (d) CO, DPPP, NEt3, Pd(OAc)2, MeOH/DMF, 80 °C, 18 h; (e) (i) LiOH, dioxane/H20, rt, 18 h, (ii) 1 M HCI (aq).
Scheme 7<sup>a</sup>
Scheme 7a
aReagents and conditions: (a) Mel, K2C03, DMF, rt, 12 h; (b) Ac20, TEA, DMAP, DCM, rt, 12 h; (c) 4-methylpent-1 -ene, P(o-tolyl)3, Pd(OAc)2, NEt3, DMF, 100 °C, 18 h; (d) H2, 10% Pd/C, EtOH, rt, 1 h; (e) (i) LiOH, dioxane/H2O, rt, 18 h, (ii) 1 M HCI (aq); (f) (CH3)2NH, MeOH, 0 °C then rt 1 h; (g) Tf20, NEt3, DCM, −10 °C, 2 h; (h) HCOOH, NEt3, Pd(PPh3)4, DMF, 80 °C, 18 h.
Scheme 8<sup>a</sup>
Scheme 8a
aReagents and conditions: (a) 4-Methylpent-1-yne, NHEt2, Cul, Pd(PPh3)2Cl2, 45 °C, 18 h; (b) H2, 10% Pd/C, rt, 18 h; (c) (i) f-BuLi, 0 °C, 1h, (ii) methyl chloroformate, −78 °C then rt 1 h; (d) 2 M HCI (aq), MeOH; (e) (i) LiOH, dioxane/H2O, rt, 18 h, (ii) 1 M HCI (aq); (0 4-Methylpent-1-ene, P(o-tolyl)3, Pd(OAc)2, NEt3, DMF, 100 °C, 18 h; (g) H2S04, AcOH/H2Q (3:1), 118 °C, 24 h; (h) H2, 10% Pd/C, EtOAc, rt, 18 h.
Scheme 9<sup>a</sup>
Scheme 9a
aReagents and conditions: (a) Styrene, P(o-tolyl)3, NEt3, Pd(OAc)2, DMF, 100 °C, 18 h; (b) (i) NaOH (aq), THF/H20, reflux or dioxane/H20, rt, (ii) 2 M HCI (aq); (c) H2, 10% Pd/C, THF or dioxane, rt, 18 h; (d) NHMe2, 0 °C, 2 h; (e) Tf20, NEt3, DCM, −10 °C, 2 h; (0 CO, DPPP, NEt3, Pd(OAc)2, MeOH/DMF, 80 °C, 24 h; (g) (i) LiOH, dioxane/H20, rt, 18 h, (ii) 1 M HCI (aq).
Scheme 10<sup>a</sup>
Scheme 10a
aReagents and conditions: (a) Meldrum’s acid, piperidinium acetate, EtOH, rt 20 min, then reflux 2 h.
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