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Classics in Chemical Neuroscience: Memantine Shahrina Alam, Kaelyn Skye Lingenfelter, Aaron M. Bender, and Craig W Lindsley ACS Chem. Neurosci., Just Accepted Manuscript • DOI: 10.1021/acschemneuro.7b00270 • Publication Date (Web): 24 Jul 2017 Downloaded from http://pubs.acs.org on July 25, 2017

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ACS Chemical Neuroscience

Classics in Chemical Neuroscience: Memantine Shahrina Alam,1 Kaelyn Skye Lingenfelter,1 Aaron M. Bender,1 and Craig W. Lindsley*1,2,3

1

2

3

Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States

Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States

Department of Chemistry, Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37232, United States

ABSTRACT: Memantine was the first breakthrough medication for the treatment of moderate to severe Alzheimer’s disease (AD) patients, and represents a fundamentally new mechanism of action (moderate-affinity, uncompetitive, voltage-dependent, N-methyl-D-aspartate (NMDA) receptor antagonist that exhibits fast on/off kinetics) to modulate glutamatergic dysfunction. Since its approval by the FDA in 2003, memantine, alone, and in combination with donepezil, has improved patient outcomes in terms of cognition, behavioral disturbances, daily functioning and delaying time to institutionalization.

In this review, we will highlight the historical

significance of memantine to AD (and other neuropsychiatric disorders) as well as provide an overview of the synthesis, pharmacology and drug metabolism of this unique NMDA uncompetitive antagonist that clearly secures its place amongst the Classics in Chemical Neuroscience. Keywords: Memantine, 3,5-dimethyladamantan-1-amine hydrochloride, Alzheimer's disease, N-methyl-D-aspartate (NMDA) receptor, Uncompetitive antagonist, glutamatergic dysfunction

BACKGROUND Alzheimer’s disease (AD) is a devastating neurodegenerative brain disorder first described in 1906 by German psychiatrist Alois Alzheimer.1,2 In the United States alone, 5.2 million people were estimated to have AD as of 2014, and was the sixth leading cause of death in the country that year.3 The total cost of treatment is also staggering, and estimated sales of

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marketed treatments in the United States totaled $2.4 billion in 2013, a figure that is expected to more than triple over the next decade.4 Worldwide, the number of patients with AD is expected to reach roughly 42 million by 2020, primarily affecting individuals in China, the developing western Pacific, western Europe, and the United States.5 In 1976, a landmark editorial by Robert Katzman highlighted AD as the world’s leading cause of dementia, and a major public health issue.6 AD progression is now characterized as early, mild to moderate, moderate to severe and advanced, with death as the ultimate outcome. Importantly, no disease modifying therapies are available.7 AD is the predominant source of dementia, a syndrome that encompasses cognition, memory, language and problem-solving; however, as AD advances, severe behavioral disturbances emerge (hallucinations, delusions, wandering and vocal outbursts) along with a loss of function (inability to swallow or walk) that typically require caregivers to institutionalize the AD patient. Thus, more so than any other CNS disorder, AD impacts both the patient and caregivers to a tremendous degree.8,9 The Alzheimer’s Association estimates that ~5.5 million people are living with AD in the Unites States today (5.3 million over 65 and ~200,000 with early onset AD). Age 65 and beyond represents the greatest risk of AD, and the population is aging with an exponential risk of developing AD (e.g., 44% of people aged 75-84 have AD). Thus, by 2035, the AD population is projected to increase from 5.5 million to 7.1 million, and by 2050, the number will increase to 13.8 million in the Unites States alone.3 O MeO O

MeO N

O

N 1, donepezil

2, rivastigmine

MeO H2N O

N

H HO 3, galantamine


4, memantine

N

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Figure 1. Structures of FDA approved acetyl cholinesterase inhibitors donepezil (1, Aricept®, FDA approved on November 25, 1996), rivastigmine (2, Exelon®, FDA approved on April 21, 2000) and galantamine (3, Razadyne®, FDA approved on February 28, 2001) and the NMDA uncompetitive antagonist memantine (4, Namenda®, FDA approved on October 16, 2003).

No therapeutics were approved for AD until 20 years after Katzman’s seminal editorial6 until the 1996 launch of Eisai’s donepezil (1, Aricept),10 the first in a series of acetyl cholinesterase inhibitors (Figure 1), whose mechanism of action is to inhibit the degradation of acetylcholine, based on the cholinergic hypothesis of the disease.11 However, acetyl cholinesterase inhibitors 1-3 are FDA approved for only the mild to moderate AD patient population (as cholinergic tone declines with disease progression and 1-3 lose efficacy), leaving moderate to severe and advanced AD patients with no treatment options.7,12 Thus, in 2003, with the FDA approval of memantine (4),13-15 a new therapeutic to address excitotoxicity in AD by targeting pathological N-methyl-D-aspartate (NMDA) receptor hyperfunction (the glutamatergic system), was exciting, and for the first time offered a treatment option for moderate to severe AD patients.13-15 Over time, physicians began to co-prescribe memantine with cholinesterase inhibitors for greater efficacy across the spectrum of AD stages, and in 2014, Namzaric (a combo memantine/donepezil capsule) was launched.16,17 Currently, AD therapeutic approaches have been focused on the amyloid hypothesis (plaques and tangles, neuroinflammation and related strategies),18 but with little clinical success to date,19 leaving cholinesterase inhibition and NMDA receptor inhibition as the only two FDA approved mechanisms for the treatment of AD.4 In this Review, we will highlight the significance of memantine in the neuroscience and AD fields, while delving into the synthesis, pharmacology and disposition of this unique NMDA receptor uncompetitive antagonist.

CHEMICAL PROPERTIES AND SYNTHESIS Memantine 4 (CAS no. 41100-52-1, IUPAC name 3,5-dimethyladamantan-1-amine hydrochloride) is a low molecular weight adamantyl amine (MW = 179.17 or 216.76 as the mono-HCl salt)13 with only the NH2 serving as a hydrogen bond donor; however, the two methyl groups play key roles in binding to the NMDA receptor.20 The compound’s empirical formula is



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C12H12N·HCl, and is a highly water-soluble crystalline solid, with a melting point of 258 oC and a cLogP of 3.0.13 Moreover, 4 complies with Lipinski’s rules and the CNS MPO score,21 translating into a highly favorable disposition profile and CNS penetration (vide infra).

The

original synthesis of memantine (4) was disclosed by Gerzon and co-workers (Scheme 1).

22-24

Bromination of 1,3-dimethyl adamantane (5) under reflux conditions gives 1-bromo-3,5dimethyl adamantane (6), which is acylated with acetonitrile in sulfuric acid (Ritter reaction) to obtain N-acetamido-3,5-dimethyl adamantane (7). Compound 7 is further hydrolyzed to liberate the free amine, and converted to memantine as the hydrochloride salt (4).

Scheme 1. Original synthesis of memantine (4) from 1963.

After product launch, several alternative process routes were developed, with one such approach highlighted in Scheme 2.25,26 Here, production of the HCl salt 4 was reduced to only three steps and avoided the use of bromine (and by-product bromine vapor) with an overall yield of 75%. In the event, direct amination of 5 with tert-BuOH/CH3CN in H2SO4 provides 7, which is hydrolyzed (PEG-400/NaOH/130-135 oC) to the primary amine and converted to the HCl salt 4.

Scheme 2. Streamlined process route of memantine (4).


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Another interesting route toward the synthesis of 4 was disclosed in 2015 (Scheme 3).27 In the two-step procedure, dimethyladamantane-1-carboxylic acid 8 undergoes decarboxylative azidation reaction with catalytic silver fluoride (20 mol %) and potassium thiosulfate as the oxidant. In the subsequent step, the azide 9 is reduced under standard hydrogenation conditions to give memantine as the freebase (4) in 68% overall yield.

Scheme 3. Recent two-step route to memantine (4).

MANUFACTURING INFORMATION

Memantine is the generic name of the drug 4, which is currently manufactured by Actavis, who acquired both Forest and Allergan, with Forest being the original manufacturer along with Merz (in Europe). Memantine is sold under the brand name Namenda® in both an immediate release formulation (Namenda IR®) and an extended release formulation (Namenda XR®).28 Namenda IR® is sold as 5 mg and 10 mg strength tablets as well as a 2 mg/mL oral solution (peppermint flavored). The average yearly cost for a course of therapy with Namenda IR® is $4,562, and the standard dosing regimen is 10 mg twice oral daily, although dosing regimens



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may vary depending on patient-specific requirements.4 Namenda XR® capsules are available in four strengths: 7 mg, 14 mg, 21 mg and 28 mg, with the optimal dosing regimen at 28 mg orally once a day.29 The average yearly cost for a course of therapy with Namenda XR® is $4,334, and the extended release formulation was approved on June 21, 2010.4,28 As ~70% of AD patients are on both memantine and donepezil, Actavis/Allergan launched Namzaric® a combo pill consisting of 28 mg memantine and 10 mg donepezil on December 23, 2014.30 All variants combined, memantine sales in 2017 are estimated at just under one billion dollars, but sales reached ~$1.8 billion in 2014. Moreover, multiple generic versions of memantine in the 5 and 10 mg tablets, as well as the oral solution, launched in late 2015 and early 2016. In addition to Namenda®, memantine is also sold under the names: Ebixa®, Axura® (the trade name from Merz in Germany where it was first approved for dementia in 1989), Memary® and Akatinol® among others.31

PHARMACOKINETICS AND DRUG METABOLISM Compound 4 is highly absorbed by the gastrointestinal tract with an absolute bioavailability of 100%. High variability in the estimate of absolute bioavailability has also been noted for 4, which appears to decrease with an increase in dose (149% at the 10 mg dose and 97% at the 40 mg dose). This variability has been attributed to a number of possible factors including non-linearity at lower doses, uncontrolled diet, and inaccurate IV dosing during clinical studies.32 Peak plasma levels for 4 are reached within 3-7 hours, with food appearing to have no influence on absorption rate. The terminal elimination half-life of 4 in man is between 60-80 hours, despite very low plasma protein binding (45%); however, a high volume of distribution is also noted (Vd = 9-11 L/kg). The CYP450 system has a negligible role in the metabolism of 4, and no inhibition or induction of the major CYPs (3A4/5, 1A2, 2D6, 2C9) were noted. Also, no drug-drug interactions (DDIs) were found, and co-administration studies with donepezil found no DDI potential for either agent as perpetrator or victim. However, there may be a small effect on compounds metabolized predominantly by CYP2B6.

Memantine is

predomantly eliminated via renal excretion, with 57 – 82% of the total dose eliminated in the urine without any structural change. As such, patients with compromised renal function must alter their dosing regimen.33


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Freudenthaler and colleagues have examined the effects of variations in urine pH and urine flow on memantine elimination. In this study, 12 healthy males were categorized to different sequences of the following groups: i) acidified urine pH and reduced urinary flow; ii) acidified urine pH and increased urinary flow; iii) alkalinized urine pH and reduced urinary flow; and iv) alkalinized urine pH and increased urinary flow. The study was performed by maintaining a steady-state concentration of 4 over a defined period of time, then altering the urinary state for a 1-day period. Each period was separated by a wash-out phase. The resulting alkalization of the urine led to decreased renal excretion and renal clearance, possibly originating from reduced renal reabsorption. The renal clearance decreased to a mean of 19.4 – 30.5 ml/min versus a mean of 148.6 ml/min without alterations, whereas acidification increased the renal clearance to 223.3 – 234.3 ml/min.34

Figure 2. Structures of major metabolites of 4. While the 6-OH metabolite 11 is shown, some sources describe a regioisomeric mixture of the 4- and 6-OH metabolites.

Three major metabolites of 4 have been characterized, and include an N-glucuronide conjugate 10, 6-hydroxymemantine 11 and 1-nitroso memantine derivative 12 (Figure 2). All of these metabolites have been found to have minimal NMDA receptor activity.33

The dose/plasma concentration relationship was found to be linear over a range of 10–40 mg in healthy volunteers. The mean maximum plasma concentration (Cmax) after a single dose of memantine (20 mg) in three trials for healthy volunteers (age 18-36 years, n = 6–23) was 24–29 µg/L (0.13–0.16 µmol/L), reached in a mean time (tmax) of 3.3–6 hours, while the area under the plasma concentration-time curve from time zero to infinity (AUC∞) was found to be 1716–2498 µg • h/L (9.3–13.5 µmol • h/L). In older healthy volunteers (n = 22, mean age 57) similar mean



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Cmax (24 µg/L [0.13 µmol/L]), Tmax (6.6 hours) and AUC∞ (2174 µg • h/L [11.7 µmol • h/L]) values were observed after a single 20 mg dose. The DMPK parameters for 1 from a 2009 study in 16 healthy male volunteers are summarized in Table 1.35 Table 1. In vivo Pharmacokinetic Properties of 1 in Healthy Volunteers.a Parameter

Memantine

Tmax (h)

6.69 ± 3.23

Cmax (ng mL-1)

12.2 ± 2.5

AUC0→∞(ng h mL-1)

989 ± 260

MRT (h)

84.7 ± 13.2

t1/2 (h)

60.5± 8.8 a

Results are expressed as mean ± SD (n = 16)

Recently, Mehta and co-workers demonstrated that memantine transport across the blood-brain barrier, at least in mouse, is mediated by the cationic influx H+ antiporter OCTN1, and CNS exposure can be reduced in the presence of other cationic compounds.36


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PHARMACOLOGY

Figure 3. A) Cartoon structure of the NMDA receptor highlighting the critical modulatory sites. B) Structures of the co-agonists glycine (13) with glutamate (14) or NMDA (15) and well characterized non-competitive NMDA antagonists 16-18 with long ‘dwell’ times and severe adverse events. Adapted from ref. 37

Due to the pioneering work of Lipton,37-40 Parsons41-43 and others, it is clear that memantine (4) is unique – a panacea amongst NMDA receptor antagonists. Memantine alone has been shown to block excitotoxic cell death in a clinically acceptable manner by targeting only



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the pathological (overactive) state of the NMDA receptor while leaving physiological states active (allowing necessary signal transduction).37,44 At a high overview level, memantine is an uncompetitive, voltage-dependent NMDA receptor antagonist with moderate affinity and fast onoff kinetics with greater efficacy in more severe excitotoxic/disease scenarios.37 The NMDA receptor is one of three classes of ionotropic (glutamate-gated ion channels), along with AMPA and kainate receptors.45 Overstimulation of NMDA receptors (NMDA hyperfunction) is involved in numerous neurodegenerative diseases such as AD, multiple sclerosis, Parkinson’s disease (PD), Huntington’s disease (HD), multiple forms of dementia, neuropathic pain, stroke, amyotrophic lateral sclerosis (ALS) and seizures while NMDA hypofunction is associated with schizophrenia.37 The NMDA receptor (Figure 3) is a heteromeric complex composed of different NR1 and NR2 subunits (NR3 subunits have recently been identified).46 For the channel to open, the obligatory co-agonists glycine (on the NR1 subunit) and glutamate (on the NR2 subunit) must bind to the NMDA receptor to release Mg2+ block and allow calcium to enter the cell.37 Under physiological conditions and normal neurotransmission, the NMDA receptor is open for milliseconds to release Mg2+ blockade and allow calcium to flow into the nerve cell. Over-activation of the NMDA receptor, such as in pathological situations, allows the nerve cell to be flooded with excessive calcium, due to prolonged channel opening, that leads to excitotoxic damage and death.

Thus, to be clinically relevant, an NMDA receptor antagonist must

selectively block pathological over-activation of the NMDA receptor, while not inhibiting normal physiological function to avoid adverse effects (e.g., a therapeutic index).37-40 The first NMDA receptor antagonists developed bound at the glutamate binding site on the NR2 subunit, hence competitive, and blocked both physiological/normal and pathological states of the receptor, leading to serious adverse events.47 Next came uncompetitive NMDA receptor antagonists, such as MK-801 (16), PCP (17) and ketamine (18) which bind within the ion channel pore region at the Mg2+ site, exposed after receptor activation. However, these first generation uncompetitive antagonists were tight binders with slow off-rates, leading to long dwell times and persistent inactivation which also disrupts normal NMDA receptor function. As a result, 16 and 17 induce psychotomimetic effects, memory disruption and other serious adverse events. Ketamine (18) has a reduced dwell time, relative to 16 and 17, which enables it to find utility as an anesthetic and as a novel treatment for depression.40,47 Although 4 and other NMDA channel blockers such as ketamine share a broadly similar mechanism of action, it is clear that


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subtle differences in the inhibitory mechanisms play a crucial role in the observed side effect profiles. Namely, memantine is an uncompetitive, voltage-dependent NMDA receptor antagonist with moderate affinity and fast on-off kinetics which preferentially targets the pathological state of the NMDA receptor while leaving normal, physiological states of the NMDA receptor uninhibited (normal neurotransmission). As a result, memantine (4) has a large therapeutic index (safety window), and has proven to be well-tolerated in man. While 4 binds to the same site as 16-18 (but preferentially to the Mg2+ binding site of the NR1 subunit), it is a low affinity, openchannel blocker with a fast off rate, a unique pharmacological profile that has proven hard to replicate since its discovery.48 Radioligand binding assays have demonstrated a Ki for 4 at ~1 µM, whereas 16-18 are generally more potent.42,49 Beyond the NMDA receptor, 4 has also been shown to inhibit nicotinic receptors (α9/α10, α7 and α4β2), the sigma -1 receptor, the 5-HT3 receptor, and block serotonin and dopamine uptake as well as dopamine release; however, in the therapeutic range (from CSF sampling), uncompetitive NMDA receptor inhibition is thought to still be the dominant mechanism of action.50,51

Figure 4. Structures of amantadine 19 (the progenitor of memantine) and TMAa (20) along with neramexane 21(the most advanced memantine analog to date).

As eluded to earlier, the methyl groups of 4 are critical for its unique activity at NMDA receptors. In a 2013 study, Dougherty and co-workers evaluated side-by-side memantine 4 and amantadine 19 (Figure 4) against wild-type NMDA receptors and a number of mutant NMDA receptors.20 Under their assay conditions, 4 possessed an IC50 of 0.54 µM, whereas 19 was much weaker (IC50 = 41 µM).

The addition of a third methyl group, to generate the symmetrical

TMAa (20), was intermediate in NMDA inhibitory activity (IC50 = 3.5 µM) between 4 and 19, highlighting the subtle differences leading to the desired uncompetitive NMDA receptor



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antagonist profile of 4. In the same study, by surveying a large number of NMDA receptor mutants, the team identified two hydrophobic pockets formed by N1-A645 and N2-A644 on the third transmembrane helices of GluN1 and GluN2B, respectively that house the two methyl groups of 4.20 The only attempt to mimic 4 that has come close is neramexane (21), a pentamethyl aminocyclohexane (Figure 4), which binds at the memantine site with similar affinity and has advanced in to clinical trials.52

EFFICACY AND ADVERSE SIDE EFFECTS

Memantine has proven clinically effective in multiple domains of moderate-to-severe AD, but failed to show significant benefit in mild AD.53 Multiple trials have supported the efficacy of 4 in AD patients with improvements in cognition, reducing behavioral disturbances, improved global function assessments and delaying the time to institutionalization.54,55 Although the effects of memantine in these trials are often considered statistically significant compared to placebo, it should be noted that the drug’s effectiveness at improving a patient’s quality of life can be inconclusive or marginal.55,56 Beyond AD, 4 showed positive trial outcomes in vascular dementia (severe had better results than mild),57 and mixed results in HIV-associated dementia.58 Clinical trials have been completed for ALS (no evidence for efficacy)59, lupus (no significant cognitive improvement)60, PD and dementia with Lewy bodies (positive results for the latter)61, schizophrenia (improvement in negative and positive symptoms as an add-on to clozapine)62, obsessive-compulsive disorder (some patient improvement in a small sample size)63, co-morbid depression and alcoholism (similarly effective to escitalopram with regards to drinking).64 Other clinical trials are being considered, or in progress today, for adjunctive autism therapy (significant improvements in open-label use for language function and social behavior)65, and generalized anxiety disorder (GAD) (no significant response)66 among others. Interestingly, memantine has also proven effective as a cognitive dysfunction-slowing agent in patients undergoing whole-brain radiotherapy.67

Due to its unique pharmacological mechanism of action, classical NMDA-related psychotomimetic events are not present in patient populations with prescribed dose, but these can be elicited upon very high acute dosing in preclinical species. Memantine has been evaluated in


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eight double-blind placebo controlled dementia clinical trials alone, where ~2,000 patients were treated for over 28 weeks. From these trials, adverse events experienced were similar in the group receiving 4 (10.1%) and the group receiving placebo (11.5%). The most common adverse events (defined as with incidence >5% of placebo) were headache, confusion, constipation and dizziness. The side effect profile of 4 is therefore considered to differ from other NMDA receptor antagonists in a quantitative aspect. For instance, in a comparison of the neuroprotective and synaptic plasticity impairing potency of memantine and (+)-MK-801 in vitro and in vivo, 4 showed a therapeutic index ratio versus MK-801 of 3.1 in vitro and 5.4 in vivo. Overall, 4 has proven to be a safe and effective medication.32,41

HISTORY AND IMPORTANCE IN NEUROSCIENCE

As mentioned previously, memantine is a panacea amongst NMDA receptor antagonists, displaying the ideal profile: an uncompetitive, voltage-dependent NMDA receptor antagonist with moderate affinity and fast on-off kinetics.37 It would be virtually impossible to rationally design and develop such a ligand today, and there have been many attempts to build a better memantine, as judged by the data with 19-21. Moreover, the story that led to memantine is a serendipitous one, and fortunately for AD patients, a very successful odyssey.

As a chemotype, amantadine (19) was the progenitor of 4, and originally introduced in the 1960s as an antiviral (influenza) medication. Serendipitously, a lone patient on 20 for her flu infection noted improvements in her PD symptoms.68 This observation led to additional studies and approval of 19 for the treatment of PD as Symmetrel®, although its utility for influenza has languished.

Thus, this chemotype and chemical class was recognized to have utility for

neurodegenerative disorders in 1969.68 Memantine (4) was first synthesized in 1963 by researchers at Eli Lilly as a building block to prepare a series of N-arylsulfonyl-N’adamantylureas as putative blood sugar lowering agents (anti-diabetics).22 While proven to be ineffective, the data with 19 undoubtedly led researchers at Merz to evaluate functionalized variants of 19 for CNS activity, such as 4. Thus, in 1972, Merz and Co. filed patent applications



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(which were granted in 1975 and 1978, in Germany and the US, respectively) for 4 (code D 145) with CNS activities relevant to PD and other cerebral disorders.24,41 The NMDA receptor pharmacology was not discovered until after clinical trials had initiated, but successful trials led to the approval of 4 in Germany in 1989 under the brand name Axura® and the INN name memantine. Merz then partnered in 2000 with Forest labs to develop 4 for AD in the United States, which was approved by the FDA in 2003 as Namenda®. Importantly, this was the only non-cholinergic medication for AD, and the only approved to treat moderate to severe AD patients. Merz later partnered with Lundbeck, to capitalize on the European market under the trade name Ebixa®, and with Suntory in Japan. By 2014, sales of 4 exceeded 1.8 billion worldwide, and Actavis acquired both Forest and Allergan, leaving Actavis the major supplier of Namenda® and Namzaric®.13,29-32

Before its various approvals, the mechanism of memantine was the subject of much debate. With the initial observation that 4 could improve symptoms in PD patients, it was logically assumed that the drug was acting via a dopaminergic or anticholinergic mechanism. It wasn’t until at least a decade following this discovery that 4 was found to be an NMDA receptor antagonist at its clinically relevant dosage. Further work at Merz indicated that the drug was a potent NMDA receptor inhibitor, while subsequent radioligand binding studies have indicated that the compound is only weakly potent (~ 1 µM) at the NMDAR. Memantine’s micromolar activity rendered it unattractive for further development by Big Pharma, and it was only because of later work by Lipton and others that highlighted the compound’s robust selectivity and specificity.37,40,69

Memantine is a classic in chemical neuroscience for several reasons. Its robust efficacy in patients led to a careful examination of the compound’s unique pharmacology: an uncompetitive, voltage-dependent NMDA receptor antagonist with moderate affinity and fast on-off kinetics. This mechanism places memantine in a delicate balance that offers selective inhibition of the pathological state of NMDA receptors without inhibiting physiological/normal NMDA receptor function. Additionally, upon its approval in 2003, 4 was the first novel mechanism, beyond acetylcholinesterase inhibition, for the treatment of AD, and the only approved therapy for moderate to severe AD. Thus, 4 filled an unmet medical need which has recently been further


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expanded across all stages of AD by the combination pill, Namzaric®. Without question, memantine is a classic in chemical neuroscience that intrigues pharmacologists and medicinal chemists, while benefiting patients.

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]. ORCID Craig W. Lindsley: 0000-0003-0168-1445

AUTHOR CONTIBUTIONS S.A., K.S.L., A.M.B., C.K.J., and C.W.L. all researched and wrote sections of this review manuscript.

FUNDING This work was funded by the NIH and NIMH (Grants MH082867 and MH106839).

NOTES The authors declare no competing financial interest.

ACKNOWLEDGEMENTS We thank William K. Warren, Jr., and the William K. Warren Foundation who funded the William K. Warren, Jr. Chair in Medicine (to C.W.L.).

ABBREVIATIONS NMDA, N-methyl-D-aspartate; IR, immediate release; XR, extended release; AD, Alzheimer’s disease; PD, Parkinson’s disease



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Memantine - ACS Publications

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