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 12.2

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.

12.2. PHARMACOLOGY OF THE NR2 GLUTAMATE BINDING SITE

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.

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.

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

12.5.2. 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.

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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