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Van Dongen AM, editor. Biology of the NMDA Receptor. Boca Raton (FL): CRC Press/Taylor & Francis; 2009.

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Biology of the NMDA Receptor.

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Chapter 12Pharmacology of NMDA Receptors

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12.1. INTRODUCTION

The discovery of NMDA receptors (NMDARs) was made possible by the synthesis and study of NMDA (Figure 12.1) and various NMDAR antagonists by Jeff Watkins and colleagues [1]. These compounds, most notably (R)-α-aminoadipate ((R)-α-AA) and (R)-2-amino-5-phosphonopentanoate (Figure 12.2), were shown to block neuronal responses to applied NMDA, but not to block responses to kainate or quisqualate [2,3]. As a result, NMDARs were shown to represent a distinct subpopulation of excitatory amino acid receptors.

FIGURE 12.1. Structures of NMDAR agonists interacting with the glutamate binding site on the NR2 subunit.

FIGURE 12.1

Structures of NMDAR agonists interacting with the glutamate binding site on the NR2 subunit.

FIGURE 12.2. Structures of NMDAR antagonists interacting with the glutamate binding site on the NR2 subunit.

FIGURE 12.2

Structures of NMDAR antagonists interacting with the glutamate binding site on the NR2 subunit.

Over the next several years, these and other NMDAR antagonists led to the discovery that NMDARs play key roles in synaptic transmission, synaptic plasticity, learning and memory, neuronal development, excitotoxicity, stroke, seizures, and many other physiological and pathological processes. These studies generated great excitement about the potential use of NMDAR antagonists to treat neuropathological and neurodegenerative diseases. However, with the exception of the use of memantine for Alzheimer’s disease, the development of NMDAR-targeted therapeutics has been disappointing. Several agents failed in clinical trials due to adverse effects and/or a lack of clinical efficacy. Despite this disappointment, NMDAR therapeutics continue to exhibit significant potential. Of the multiple drug binding sites on the various NMDAR subunits, many potential types of NMDAR antagonists exist, and some of these reveal distinct patterns of selectivity. This chapter will summarize the current understanding of the various sites of drug action on the NMDAR complex.

NMDARs are heteromeric complexes composed of four subunits derived from three related families: NR1, NR2, and NR3 subunits [4–6]. The well-characterized glutamate- and glycine-responsive NMDAR requires both NR1 and NR2 subunits. The NR1 subunit contains a glycine binding site [7,8], while the homologous domain on the NR2 subunit contains the (S)-glutamate binding site [9,10]. Multiple lines of evidence suggest that a single NMDAR complex contains two NR1 subunits and two NR2 subunits [11]. The NR3 subunit can complex with NR1 subunits to form a glycine-responsive excitatory receptor that does not require L-glutamate [12].

The NR1 subunit gene consists of 22 exons; exons 5, 21, and 22 can be alternatively spliced to produce eight distinct NR1 isoforms [13,14]. As discussed below, exon 5 of NR1 inserts a 21-amino acid sequence in the N-terminal extracellular domain that significantly alters receptor responses to pH and polyamines such as spermine [15]. The other two alternative splice cassettes are at the intracellular C terminus and do not affect NMDAR pharmacological properties [14]. The three NMDAR families (NR1, NR2, and NR3) display 27 to 31% identity to each other. Within the NR2 family, NR2A and NR2B are more closely related to each other (57%) than to NR2C or NR2D (43 to 47%), which are closely related to each other (54%). Thus, with respect to the NR1/NR2 NMDAR complex, the pharmacological heterogeneity is primarily determined by the NR2 subunit and exon 5 of the NR1 subunit.

NMDAR pharmacology has its basis in the domain structure of the NMDAR subunits. Each subunit is composed of an extracellular amino terminal, four hydrophobic segments (M1 through M4), and an intracellular carboxy terminal [5,6]. Each subunit contains two regions that have homology to bacterial amino acid–binding proteins. The first 350 amino acid residues contain the amino terminal domain (ATD) that has homology to the bacterial amino acid–binding protein known as LIVBP (leucine–isoleucine–valine binding protein) [16,17]. This region is thought to be an allo-steric regulatory domain that binds zinc in NR2A and polyamines in NR2B [18–20].

The second structure with homology to bacterial amino acid–binding proteins is the glutamate–glycine binding domain formed by the pairing of two discrete segments, S1 and S2. S1 is a sequence of 120 amino acids located between the ATD and the first transmembrane domain (M1). The S2 segment is found on the extracellular loop between the third and fourth hydrophobic domains (M3 and M4). Together, S1 and S2 form a bilobed structure with structural homology to the bacterial leucine–arginine–ornithine binding protein (LAOBP) [21]. The (S)-glutamate and glycine binding sites are found in the cavity between the two lobes of the S1/S2 structure in NR2 and NR1 subunits, respectively.

The ion permeating channel represents an additional drug binding site, a binding site for NMDAR channel blockers such as PCP, MK-801, and memantine (Figure 12.3). The channel structure is structurally related to potassium channels wherein one hydrophobic segment forms a P loop within the membrane and this segment is flanked by transmembrane domains [22,23]. The P loop contributes to the selectivity filter of the channel. Near the tip of this loop is a critical asparagine residue that is important for the binding of several channel blockers. The other transmembrane domains contribute to the pore lining in the extracellular facing half of the membrane and thus can contribute to channel blocker binding.

FIGURE 12.3. Structures of antagonists that bind to a site inside the channel of NMDAR complex.

FIGURE 12.3

Structures of antagonists that bind to a site inside the channel of NMDAR complex.

12.2. PHARMACOLOGY OF THE NR2 GLUTAMATE BINDING SITE

12.2.1. Agonists

Early structure–activity studies established that an ideal structure for activating NMDARs (and for activating EAA receptors in general) is represented by (S)-glutamate [1]. Excitatory activity requires one positive and two negative charge centers. The positive charge center (e.g., NH3+) should be positioned α to a carboxyl group. For optimal agonist action, the two negative charge groups (preferably both carboxylic acids) should be separated by four carbon–carbon bond lengths, and the α carbon should be in the S configuration. These findings are consistent with the three-point attachment pharmacophore model proposed by Curtis and Watkins [24] and recently confirmed by the publication of the X-ray crystal structure of glutamate bound to the ligand binding core of NR2A [25]. The ω acid group can also be a sulfonate or a tetrazole. In the latter case, the carbon chain should be shorter, (as in the very potent tetrazol-5-glycine NMDAR agonist [26] (Figure 12.1).

NMDA is several-fold weaker as an agonist than (S)-glutamate. However, NMDA has a low affinity for the plasma membrane transporters and thus can appear more potent than glutamate in some physiological assays. It is perhaps surprising that such a simple structure as NMDA is so selective; in the micromolar range, NMDA displays no activity at other glutamate receptors. The critical difference between NMDARs and the non-NMDA ionotropic glutamate receptors that allow NMDA to bind in the NR2 subunit binding pocket is an aspartate residue (D731 in NR2A) that is a glutamate residue in the AMPA and kainate receptors. This residue binds the agonist’s amino group and by being one methylene group shorter in the NR2 subunit, allows space for the N-methyl group of NMDA [25].

By incorporating ring systems into the glutamate structure, rigid glutamate analogues that are potent NMDAR agonists have been developed. They mimic the active, partially folded, conformation of (S)-glutamate and include homoquinolinate [27], (2S,1′R,2′S) 2-(carboxycyclopropyl)glycine (L-CCG-IV) [28,29], (1R,3R) 1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) [30], and 1-aminocyclobutane-1,3-dicarboxylic acid (ACBD) [31–33]. See Figure 12.1 for structures. With resolution of the NR2A crystal structure with (S)-glutamate bound, the precise features that underlie high affinity (S)-glutamate binding are now known [25].

12.2.2. Antagonists

The first NMDAR antagonists were variations of the (S)-glutamate structure. For example, by extending the glutamate backbone by one carbon, antagonist activity was observed for (RS)-a-AA [34]. Antagonist activity arose from the (R) isomer [2,35]. (R)-α-AA (Figure 12.2) was found to inhibit NMDA-evoked depolarizations while having little effect upon kainate- or quisqualate-evoked responses [1,2,36]. Hence, NMDA was shown to activate a receptor that is distinct from those activated by kainate or quisqualate. Even greater antagonist potency was found by replacing the ω carboxy group of (R)-α-AA with a phosphonate group, resulting in (R)-2-amino-5-phosphonopentanoate ((R)-AP5 or D-AP5, Figure 12.2) [37–39], also known as D-2-amino-5-phosphonovalerate (D-APV). For both (R)-α-AA and (R)-AP5, extending the chain length by adding a –CH2 group diminished affinity, yet adding two carbons to the chain restored potency ((R)-α-aminosuberate and (R)-2-amino-7-phosphonoheptanoate (Figure 12.2), respectively).

As found for agonists, glutamate binding site antagonists display at least three charge centers, one positive and two negative [33]. The two negative charge centers are generally provided by a carboxyl group that is α to an amino group and by a distal acid group that is frequently a phosphonate group. The positive charge center can be provided by a primary or secondary amine. The distal phosphonate group may provide two charge–charge interactions with a receptor since phosphonates provide significantly greater affinity than a corresponding carboxylate or sulfonate [40]. The ω phosphonate group of NMDAR antagonists can sometimes be replaced by a tetrazole [41], but this modification reduces potency. The chiral carbon attached to both the carboxyl and amino groups generally should be in the R configuration.

Further increases in antagonist potency can be achieved by constraining the AP5/AP7 chain in various ring structures and by adding specific groups (bulky hydrophobic groups, methyl groups, or double bonds) to this backbone. Several potent and selective NMDAR antagonists are generated by incorporating the AP5 or AP7 backbone into a piperidine or piperazine ring (see Figure 12.2 for structures). Hence, 4-phosphonomethyl-2-piperidine carboxylic acid (CGS19755) [42] is a potent AP5 analogue where the amino group is part of a piperidine ring, and 4-(3-phosphonopropyl) piperazine-2-carboxylic acid (CPP) [43,44] is a potent AP7 analogue incorporated into a piperazine ring (Figure 12.2). A further increase in potency results when a double bond is introduced into the carbon chain of D-CPP to make D-CPPene [(R,E)-4-(3-phosphonoprop-2-enyl) piperazine-2-carboxylic acid] [45].

A variety of other ring structures and additional groups have also been shown to increase the antagonist potency of the basic AP5/AP7 structure. The addition of a cyclohexane ring (NPC 17742) [46], biphenyl group (EAB 515) [47], methyl group plus a double bond (CGP 37849) [48], and quinoxaline ring [49] all yield compounds of increased affinity for NMDARs. Unlike the parent compound, the ethyl ester of CGP 37849, CGP 39551 displayed oral bioavailability as an anticonvulsant, presumably acting as a prodrug form of CGP 37849 [48].

A photoaffinity probe has been developed based on the structure of CGP 39653 [50]. NMDAR antagonists with benzene rings include a variety of phenylglycine and phenylalanine derivatives with a wide range of potencies [33]. The incorporation of the unsaturated bicyclic decahydroisoquinoline ring or a partially unsaturated tetrahydroisoquinoline ring into the AP7 backbone produced a wide variety of NMDAR antagonists of varying activities [51]. The phosphono derivative LY 274614 was the most potent. Interestingly, some of these compounds display distinctive NMDAR subtype selectivities [52,53]. A number of radioligands have been developed, e.g., [3H]AP5 [54,55], [3H]CGS19755 [56], [3H]CPP [57], and [3H]CGP 39653 [58] (KD value 7 nM). The latter is potent enough to be used in a filtration binding assay, facilitating compound throughput. These ligands, however, are limited to the labelling of NR2A- or NR2A- and NR2B-containing NMDARs. In contrast, (S)-[3H]glutamate can label all four NR2 subunits [59].

The general rules listed above for NMDAR antagonist activity have few exceptions. One example is the preference for six-bond lengths between the acidic groups to achieve optimal activity. The insertion of a chlorinated quinoxaline ring [49] into the (R)-AP6 structure results in α-amino-6,7-dichloro-3-(phosphonomethyl)-2-quinoxalinepropanoic acid (I in Figure 12.2), a highly potent NMDAR antagonist. Likewise, the addition of a cyclobutane ring into D-AP6 yields two 1-aminocyclobutanecarboxylic acid derivatives (ACPED in Figure 12.2) that are antagonists [60].

While for most potent NMDAR antagonists the R configuration at the α carbon has greater activity than the corresponding S isomer, some S isomer antagonists are more potent, for example, the EAB515-related antagonists in which a biphenyl (or triphenyl) group is incorporated into the AP7 chain. The S isomer displays higher affinity than the R isomer [61]. Likewise, the bicyclic decahydroisoquinoline LY-235959 (Figure 12.2) has greater activity associated with the S isomer [51].

Pharmacophore modeling studies describe the optimal antagonist structure as having 5.1 to 6.6 Å between the two negative charge centers [62–64]. This conforms to the straight chain, piperazine, and piperidine phosphonate antagonists such as (R)-AP5, (R)-CPP, and CGS19755. However, in the biphenyl/phenanthrene antagonists, (2R*,3S*)-1-(4-phenylbenzoyl)piperazine-2,3-dicarboxylic acid (PBPD) and (2R*,3S*)-1-(phenanthrenyl-2-carbonyl)piperazine-2,3-dicarboxylic acid (PPDA), the distance between the two carboxyl carbons is 3.4 Å (see Figure 12.2). The structure has two carboxylic acids separated by only three carbon–carbon bonds and an additional carbonyl group four bond lengths away from the amino carbon. Site-directed mutagenesis results support molecular modeling studies indicating that a histidine residue in the active site interacts with the distal carboxyl group in PPDA but does not interact with the phosphonate group in CGS19755 [65]. Thus, the pharmacophores for PPDA and CGS19755 are not identical.

12.2.3. NR2 Subunit Selectivity of Glutamate Binding Site Ligands

NR2 subunits provide the greatest potential for pharmacologically distinguishing different types of NMDARs. This subunit family is generated by four distinct genes, each coding for a slightly different glutamate binding site and different ATD regulatory sites [66–70]. They also contribute similar (but not identical) channel lining structures. In contrast, the NR1 subunits are generated by only one gene that produces identical glycine binding sites and identical channel-lining residues [71]. The exon 5 extracellular alternative splice site introduces a modified ATD region. Since NR2 subunits also confer distinct physiological and biochemical properties to NMDARs, the selective blockade of differing NR2 subunit types should yield compounds with distinct therapeutic and adverse effect profiles.

An important consideration for subunit-specific antagonists is to define their actions in a heteromeric receptor complex. Functional NMDARs are thought to consist of two NR1 subunits and two NR2 subunits [11,72], although some tetrameric NMDAR complexes may contain NR3 subunits [73]. Coimmunoprecipitation studies indicate that multiple types of NR1 subunits and NR2 subunits may be coassembled into the same receptor complex [74–76]. Physiological studies indicate that both glutamate- and glycine-binding sites must be occupied to achieve channel activation [77]. Thus, an NMDAR with both NR2A and NR2B subunits may be highly sensitive to a selective NR2A glutamate-binding site antagonist and an NR2B glutamate-binding site antagonist. Agents acting at the ATD regulate activity via domain–domain interactions; hence their actions in a heteromeric assembly may depend upon the specific complex.

Another possibility is that the subunit in the heteromeric assembly may alter the pharmacological specificities of adjacent subunits. For example, the glycine-site antagonist CGP 61594 displays nearly a 10-fold higher affinity in a complex containing NR2B subunits than those containing NR2A subunits [78]. The adjacent NR2 subunit alters the pharmacological specificity of the NR1 subunit. Similar examples can be found for kainate receptor complexes. If NR2 subunits can likewise alter the pharmacological specificity of an adjacent NR2 subunit, NMDARs may possess even greater pharmacological diversity. To date, however, studies of native NMDARs expressed in rat brains identified only four pharmacologically distinct populations of glutamate recognition sites [52,79,80]. The anatomical distribution and pharmacological profile of these four pharmacologically distinct sites correspond well to the four NR2 subunits in the brain [81–84].

No glutamate-binding site antagonists display high degrees of NR2-subunit selectivity. In a survey of more than 75 compounds at native NMDARs [85], most displayed similar weak selectivity patterns corresponding to the highest affinity at NR2A with progressively lower affinities at NR2B, NR2C, and NR2D. This is the typical pattern observed for antagonists such as (R)-AP5, (R)-CPP, and CGS-19755 [86]. Of the compounds examined, only large, multiring antagonists (biphenyl compounds EAB515 and PBPD and the bicyclic decahydroisoquinoline LY233536) displayed varied selectivity patterns confirmed via recombinant receptors [53]. Each exhibited reduced relative affinity for recombinant NR2A-containing receptors; EAB515 and PBPD had higher affinities for NR2B- and NR2D-containing receptors; and LY233536 had higher affinity for NR2B- and NR2C-containing receptors. LY233536 displayed approximately 10-fold selectivity for NR2B- over NR2A-containing receptors at both recombinant [53] and native NMDARs [82]. Nevertheless, each of these compounds displayed low levels of selectivity that limit their utility.

In characterizing a series of derivatives of PBPD, a higher affinity compound PPDA (Figure 12.2) displayed a small improvement in selectivity for NR2C- and NR2D-containing NMDARs [87,88]. PPDA has been successfully used to demonstrate that long-term potentiation and long-term depression are mediated by pharmacologically distinct NMDARs [89] and that NMDAR-mediated synaptic responses in adult hippocampal CA3-CA1 synapses have two pharmacologically distinct components [90]. This agent has been improved via a closely related compound known as UBP141 (Figure 12.2). It should be useful for distinguishing NR2B and NR2D subunit-containing NMDARs because it displays a several-fold higher affinity for NR1/NR2D receptors than for NR1/NR2B receptors and intermediate affinity for NR1/NR2A.

Another large, quinoxaline-2,3-dione based antagonist with unusual subunit-selectivity is the widely-used NR2A-selective antagonist NVP-AAM077 (Figure 12.2) [91]. It displays a 100-fold selectivity for human NR2A-containing NMDARs compared to NR2B-containing receptors. At rodent NMDARs, however, the degree of selectivity is about 10-fold [87,92–94]. NVP-AAM077 also has high affinity for NR2C subunits and lower affinity for NR2D-containing receptors [87] and thus is modestly selective for NR2A and NR2C subunits.

A major challenge in developing agents to distinguish NR2 subunits is the highly conserved aspect of the glutamate-binding pocket [65]. Of the amino acid residues that line the binding pocket, only a few are variable between NR2 subunits and all are at a distance from the central glutamate binding core. Modest differences also exist in the selectivity of small antagonists such as (R)-CPP and (RS)-4-(phosphonomethyl)-piperazine-2-carboxylic acid (PMPA, Figure 12.2) [87]. While (R)-CPP displays a 50-fold higher affinity for NR2A than for NR2D subunits, the two-carbon shorter analogue PMPA shows only a five-fold difference in affinity. Hence, the NR2 subunits appear to have structural differences in the binding pocket. Recent modeling studies suggest that the position of helix F in the S2 domain of NR2A is slightly different in NR2D [95]. This places a small groove in the NR2D subunit that can accommodate the methyl group of the agonist (2S,4R)-4-methylglutamate and thus contributes to the 46-fold higher affinity displayed by NR2D subunits for this compound.

Most agonists studied to date exhibit the reverse selectivity patterns of most small antagonists; agonists tend to have high affinities for NR2D > NR2C > NR2B > NR2A subunits. In large surveys of compounds at native NMDARs [85] and at recombinant receptors [95], homoquinolinate stands out as having higher affinity for NR2A- and NR2B-containing NMDARs.

12.3. PHARMACOLOGY OF GLYCINE BINDING SITE ON NR1

12.3.1. Agonists

Glycine binds to the S1S2 site on the NR1 subunit and is a necessary coagonist for activation of NMDARs [96,97]. Initially it was thought that endogenous levels of extracellular glycine were enough to saturate the glycine binding site; however, later studies suggest that this is not the case and it may be possible to develop positive modulators of NMDAR function via interaction with the glycine binding site [98]. Amino acids such as (R)-alanine and (R)-serine (Figure 12.4) display high affinities for the glycine site and behave as full agonists [99]. Conformationally constrained analogues of glycine such as ACPC, a cyclopropyl analogue [100,101], and ACBC, a cyclobutane analogue [102], are partial agonists with different degrees of efficacy. At lower doses, they show antischizophrenic properties in animal models but this effect is reversed at higher doses when they act like antagonists [103]. Other partial agonists include HA-966 (Figure 12.4), one of the first compounds identified as an NMDAR antagonist [36], and L-687,414 [104].

FIGURE 12.4. Structures of agonists and partial agonists that interact with the glycine binding site on NR1.

FIGURE 12.4

Structures of agonists and partial agonists that interact with the glycine binding site on NR1.

Interestingly, the cocrystal structures of the NR1 ligand binding core with the partial agonists ACPC and ACBC show the same degrees of domain closure as found in the complex with the full glycine agonist [105]. Thus the mechanism by which partial agonism occurs for the NR1 subunit is distinct from that of the related GluR2 AMPA receptor in which partial opening of the binding domains results from partial agonist binding; full agonists stabilize the closed form and antagonists the open form [106,107].

12.3.2. Antagonists

The development of antagonists acting at a glycine binding site associated with an NMDAR and the therapeutic potential of such compounds were reviewed [99] and the first full antagonist found to bind to the glycine site was kynurenic acid (Figure 12.5) [108,109]. It was nonselective and antagonized a range of glutamate receptors. The AMPA/kainate receptor antagonists designated CNQX and DNQX (Figure 12.5) [110] also act as weak NMDAR antagonists [111]. These lead compounds were used as templates to develop more potent antagonists via structure–activity relationship studies.

FIGURE 12.5. Structures of antagonists that interact with the glycine binding site on NR1.

FIGURE 12.5

Structures of antagonists that interact with the glycine binding site on NR1.

Structural modification of kynurenic acid led to a series of potent antagonists such as 5,7-dichlorokynurenic acid (5,7-DCKA) [112], L-683,344 [112], L-689,560 [113], L-701,324 [114], GV150526A [115], and GV196771A [116] (see Figure 12.5). Analogues of CNQX such as ACEA-1021 [117] (Figure 12.5) were described as potent and selective glycine site antagonists, but quinoxalinedione derivatives suffered from poor water solubility. A SAR study of the quinoxaline-2,3-dione structure provided α-phosphoalanine-substituted compounds with >500-fold selectivity for the glycine site (compared to AMPA receptors), enhanced water solubility, and excellent in vivo anticonvulsant activity [118]. Pharmacophore models for the NMDAR glycine site [99,119,120] have been superseded by X-ray crystal structures of antagonists bound to the ligand binding core of NR1 [121].

Glycine site antagonists have improved therapeutic ratios (retain anticonvulsant, neuroprotective, and analgesic properties and exhibit reduced psychotomimetic effects) in comparison to conventional orthosteric antagonists [99]. However, the brain bioavailability of these compounds is questionable (high affinity plasma protein binding is the main problem) [122]. None of these compounds have achieved clinical use to treat stroke or epilepsy. Recently, a range of antagonists based on the quinoline nucleus (II in Figure 12.5) have been developed and dosed orally displayed good aqueous solubility and excellent bioavailability based on plasma concentration and activity in an in vivo model of neuropathic pain [123].

A photoaffinity label, [3H]CGP 61594 (Figure 12.5) has been developed for the NMDAR glycine site [124]. An early report indicated that CGP 61594 displayed higher affinity for the NR1/NR2B receptor subtype over NMDARs containing NR2A, NR2C, or NR2D subunits [78]. The dependency of the affinity of agonists for the glycine site of the NR1 subunit on the type of NR2 subunit in the tetrameric complex has been reported [70,125].

12.4. PHARMACOLOGY OF GLYCINE BINDING SITE ON NR3

The NR3A and NR3B subunits reveal only a 24 to 29% sequence homology with NR1 and NR2. When NR3A or NR3B subunits are coexpressed with NR1 and NR2, they act as negative modulators, reducing single-channel conductance and Ca2+ permeability [73,126]. However, when NR1 and NR3A are coexpressed in Xenopus oocytes, the excitatory glycine receptors formed are Ca2+ impermeable [12]. Whether these NR1/NR3 excitatory glycine receptors exist in neurons remains controversial. Studies using the ligand binding cores of NR1 and NR3A revealed that glycine has a 650-fold higher affinity for NR3A compared to NR1 [127]. Reports suggest that in NR1/NR3 receptors glycine binds to the NR3 subunit leading to ion channel opening while glycine binding to NR1 leads to inhibition due to rapid desensitization [128,129]. This is in contrast to the NR1/NR2 subunit combination in which glycine binding to NR1 potentiates NMDAR function. The reduced current through triheteromeric NR1/NR2/NR3 receptors may arise from inhibition via glycine binding to the NR1 subunit in the NR1/NR3 dimer (assuming the tetramer consists of a dimer of dimers).

Isolated ligand binding cores were used to investigate the pharmacology of NR3A. Interestingly glutamate can bind to NR3A with very low affinity but would not bind to NR3A at physiologically relevant concentrations [127]. The rank order of affinity for NR1 based on testing of partial agonists was ACPC > ACBC > cycloleucine. The rank order for NR3 was ACBC > ACPC > cycloleucine. Indeed, ACBC (Figure 12.5) showed 65-fold higher affinity for NR3 compared to NR1 [127]. A number of NR1 glycine site antagonists were tested and the quinoxalinedione analogue CNQX (Figure 12.5) was found to have low micromolar affinity for NR3A and ~2.5-fold higher affinity for NR3A versus NR1. Importantly, a number of antagonists with nanomolar affinities for NR1 had only low affinity for NR3A (5,7-DCKA and L-689,560, Figure 12.5), suggesting that the binding site of NR3A is different from that of NR1. It should therefore be possible to develop selective NR3A antagonists. Homology models of NR3A and NR3B provided insights into differences in the pharmacology of NR1 and NR3 [127,130]. The binding site cavity in NR3 is likely to be larger than that in NR1 because two amino acids (V689 and W731) in the NR1 ligand binding core are replaced by alanine and methionine residues, respectively. The ACPC and ACBC partial agonists (Figure 12.5) make van der Waals contacts with V689 in NR1 [105]. The replacement of this residue by an alanine residue in NR3 along with the W731M switch may explain the differences in affinities of these two agonists for NR1 compared to NR3 [127]. In addition, the W731M switch in NR3 may at least partially explain why the 5,7-DCKA NR1 antagonist has low affinity for NR3; W731 makes an important contact with the 5-chloro substituent of 5,7-DCKA in NR1.

Little is known about the functions of NR3A subunits in the CNS, although increased dendritic spine formation in early postnatal cerebrocortical neurons of NR3−/− mice has been reported [73]. Recent studies revealed that oligodendrocytes express NR3A subunit-containing NMDARs [131–133]. The NMDARs appear to be key players in glutamate-mediated damage of oligodendrocytes and show potential as new therapeutic targets to prevent white matter damage in a range of conditions. The precise subunit composition of these oligodendroglial NMDARs is unknown.

12.5. ALLOSTERIC MODULATORY SITES ON NMDA Receptors

12.5.1. Polyamines

Studies of native and recombinant NMDARs revealed three effects of polyamines on NMDAR activity: (1) glycine-dependent stimulation characterized by an increase in glycine affinity for its binding site, (2) glycine-independent stimulation characterized by increases in the maximal amplitudes of NMDAR responses at saturating concentrations of glycine, and (3) voltage-dependent inhibition. In the absence of glutamate and glycine, polyamines have no effect on NMDAR activity. However, they increase glycine affinity [134–137] and thus increase NMDAR responses at subsaturating glycine concentrations by increasing glycine association.

Under saturating glycine conditions, polyamines still potentiate NMDAR responses (glycine-independent potentiation). In addition, at negative potentials, polyamines reduce channel conductance by partial channel block. Consistent with early studies [138], these polyamine effects are noncompetitive with glutamate, glycine, and channel blockers, suggesting distinct binding sites for polyamines [139,140].

Polyamine responses are dependent upon specific NR1 and NR2 subunits. Glycine-independent stimulation by spermine in recombinant receptors expressed in Xenopus oocytes is inhibited by the N-terminal insert of the NR1 subunit coded by exon 5 [15,141,142]. The E342 residue in the amino terminus of the NR1 subunit is necessary for glycine-independent spermine stimulation [143] but has no effect upon polyamine glycine-dependent potentiation or voltage-dependent channel block. Mutations at equivalent positions in NR2A and NR2B subunits had no effect on spermine stimulation.

The NR2 subunit also contributes to both the stimulatory and inhibitory effects of polyamines at NMDARs [144–146]. Polyamines cause glycine-independent stimulation and decrease the affinity for glutamate site agonists at NR1a/NR2B receptors but not at NR1a/NR2A, NR1a/NR2C, or NR1a/NR2D receptors. However, glycine-dependent stimulation and voltage-dependent inhibition are seen at both NR1a/NR2A and NR1a/NR2B receptors. These data suggest the existence of at least three distinct polyamine binding sites on NMDARs.

12.5.2. Ifenprodil and Related NR2B-SelectIve Compounds

A large number of pharmacological agents bind and inhibit NMDAR activity specifically at NR2B-containing receptors. The prototype is ifenprodil (Figure 12.6), a phenylethanolamine that binds at a site distinct from the glutamate- and glycine-binding sites [147,148]. Ifenprodil exhibits greater than a 100-fold selectivity for NR2B over NR2A containing receptors [149] and very low affinity at NR2C- and NR2D-containing receptors [145]. The ifenprodil binding site appears to be located on the ATD region and involves amino acid residues distinct from (and possibly partially overlapping) residues that contribute to polyamine binding [150]. The NR1 insert (exon 5), which alters polyamine modulation of NMDARs had no effect on ifenprodil inhibition of NMDAR activity. This suggests that the glycine-independent polyamine binding sites on NMDARs are separate from those of ifenprodil binding sites [151].

FIGURE 12.6. Examples of polyamine site antagonists.

FIGURE 12.6

Examples of polyamine site antagonists.

A variety of other compounds show NR2B selectivity, including haloperidol [152], CP-101,606 [153], and Ro 25-6981 [154] (Figure 12.6). These compounds display the highest degree of subtype selectivity among the different classes of NMDAR antagonists. They have been useful for defining the actions of NR2B-containing receptors in the brain.

Structure–activity analysis of ifenprodil-like compounds has been explored extensively and multiple series of compounds have been optimized for selective high affinity binding. One challenge already overcome is the α-1 adrenergic receptor antagonist activity and/or human ether a go-go (hERG) potassium channel blocking activity (which may lead to cardiac arrhythmias) of many ifenprodil-like agents [155]. Another success was identifying agents that are metabolically stable and active in vivo. Several lead compounds are now providing interesting preclinical data regarding the role of NR2B subunits in neuropathic pain and excitotoxicity.

The general pharmacophore structure, as represented by ifenprodil (Figure 12.6, compound a), has two aromatic rings separated by a linker with a basic nitrogen in the center of the linker. Commonly, each ifenprodil-like compound has a 4-benzyl-piperidine group that provides one aromatic ring and the basic nitrogen. This moiety is then linked to a second aromatic ring system that optimally has a hydrogen bond donor. Thus, the potency of ifenprodil is reduced by removal of its phenol hydroxy group. This general structure is similar to those of the well-characterized NR2B antagonists, Ro-25,6981 [154] and CP-101,606 [153] (Figure 12.6, compounds b and c).

Optimization of different initial lead compounds indicates that removal of an aromatic ring or basic nitrogen can be tolerated if combined with other changes. The phenol ring can be replaced by a number of heterocyclics such as a benzimidazole [156], benzimidazolone [157], benzoxazole-2(3H)-one [158], indole-2-carboxamides [159], and aminotriazole [160], especially if they contain an H-bond donor (Figure 12.6, compounds d through h). Likewise, the linker between 4-benzylpiperidine and phenol can be replaced by number of structures. Significantly, a basic nitrogen in the linker is not essential. A nonbasic nitrogen correlated with reduced hERG and α-1 NE activity (Figure 12.6, compound i) [161]. In a series of dihydroimidazoline derivatives (Figure 12.6, compound j), replacement of a terminal aromatic group by an aliphatic chain was also tolerated, resulting in high affinity NR2B-selective antagonists [162]. A series of 4-aminoquinolines (Figure 12.6, compound k) [163] and 4-(3,4-dihydro-1H-isoquinolin-2yl)-pyridines (Figure 12.6, compound l) diverge from the original ifenprodil structure. They retain at least an aromatic ring at each end with a nitrogen in the center.

12.6. ZINC

Zinc displays subunit-specific actions at recombinant NMDARs. It displays a voltage-dependent inhibition of NMDAR responses in heteromeric NR1/NR2A and NR1/NR2B receptors. At lower concentrations, it shows a voltage-independent inhibition of NR1/NR2A receptors [164,165]. The NR2A selectivity accounts for observations that the addition of heavy metal chelators to buffer solutions significantly potentiates NR1a/NR2A but not NR1a/NR2B receptor responses. This result may be due to chelation of contaminant traces of heavy metals in solutions that tonically inhibit NR1a/NR2A NMDAR responses. Two effects of zinc were also seen in cultured murine cortical neurons [166]. At low concentrations (3 μM), it produced a voltage-independent reduction in channel open probability. At higher concentrations (10 to 100 μM), it produced a voltage-dependent reduction in single channel amplitude associated with an increase in channel noise, suggesting a fast channel block. Since zinc is co-released with glutamate from pre-synaptic terminals, zinc modulation of NMDARs may be physiologically relevant [167,168].

Molecular modeling experiments paired with site-directed mutagenesis indicate that the ATD region forms a bilobed structure with an apparent binding cavity in the center, much like that found for the glycine or glutamate binding S1/S2 domain [169]. In NR2A, specific histidine residues are necessary for zinc inhibition. Interestingly, these sites line both sides of the binding cleft in the ATD structure. This suggests that zinc binding may induce domain closure and this is transmitted to the S1/S2 domain as an inhibitory signal. The observation that zinc binding alters the trypsin sensitivity of purified ATD protein supports this model. The implications of the model are significant for potential drug development.

12.7. UNCOMPETITIVE ANTAGONISTS (CHANNEL BLOCKERS)

In the mammalian CNS, Mg2+ ions block NMDAR channels at resting membrane potentials [170]. This block is voltage-dependent. At depolarized membrane potentials, the channel block is relieved and ion fiux occurs [171,172]. Nonhomologous asparagine residues on NR1 and NR2 subunits produce a constriction in NMDAR ion channels, allowing Ca2+ but not Mg2+ ions to enter [173]. The low affinity binding site for Mg2+ ions is deep within the channel and NMDAR complexes containing NR2A or NR2B subunits have a higher affinity for Mg2+ than those containing NR2C or NR2D [66].

A number of compounds block NMDAR channels by a use-dependent (channels must be opened via binding of glycine and glutamate to their respective binding sites for access to and dissociation from the binding site) and voltage-dependent mechanism [174,175]. These compounds include the dissociative anaesthetics, phencyclidine (PCP) and ketamine [176]. Site-specific mutagenesis revealed that an asparagine residue (N598) deep within the pore lining M2 segment of an NMDAR is important for channel blocking [177]. Since the mechanism of these channel blockers is use-dependent, the suggestion was made to use them to treat ischemia in which neurons degenerate due to excessive Ca2+ entry through NMDARs. This led to the development of selective high affinity NMDAR channel blockers such as MK-801, which is used widely as an experimental tool [178,179]. The kinetic action of channel blocking and unblocking exhibited by MK-801 depends on the NR2 subunit composition of the NMDAR complex. Slower channel blocking kinetics were observed for NR2C-containing receptors compared to those containing NR2A or NR2B [180]. This is consistent with the shorter open times of NR2C-containing receptors.

High affinity channel blockers such as PCP and MK-801 induced psychotomimetic-like effects in animals. This result coupled with adverse effects such as ataxia, memory and learning impairment, and neuronal vacuolization has prevented development of high affinity channel blockers for clinical use [181,182]. The propensity of these compounds to produce adverse side effects has been linked to their slow kinetics of dissociation from their binding site in the NMDAR channel. Indeed, the slow dissociation rate of MK-801 allows it to be trapped inside the channel.

High affinity channel blockers such as PCP mimic the symptoms of schizophrenia and have served as animal models of this disorder. Low affinity channel blockers such as memantine exhibit fast on-and-off kinetics and reduced tendencies to produce adverse reactions such as psychotomimetic effects [181]. Memantine is now in clinical use under the trade names Ebixa, Axura, and Namenda for treatment of cognitive deficits in moderate to severe Alzheimer’s disease. Although it is a channel blocker, memantine exhibits three- to five-fold greater potency for NR2C- versus NR2A-containing NMDARs but the relevance of this modest subunit selectivity to the improved therapeutic profile has not been established.

12.8. CONCLUDING REMARKS

The pharmacology of NMDAR complexes is highly diverse due mainly to the complexity of the subunit composition of NMDARs. Despite many years of sustained effort in developing drugs that interact selectively with NMDAR complexes, only memantine, a low affinity channel blocker, has made it into the clinic. However, recent advances in solving the X-ray crystal structures of ligand binding cores of NR1 and NR2 subunits have made possible the development of selective agonists and antagonists for individual NR2 subunits.

In addition, advances in our understanding of the pharmacology and function of the NR3 subunit are likely to lead to the development of selective antagonists for this subunit. The combination of subunit-selective pharmacological tools for NMDARs and molecular biological methods will provide significant information about the functions of NMDARs and the roles played by the individual subunits in the CNS. In addition, these advances are likely to herald new possibilities for treating a range of CNS disorders in which NMDARs play a role.

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