Classics in Chemical Neuroscience: Memantine - ACS Publications

Alzheimer's disease (AD) is a devastating neurodegenerative brain disorder first ..... generalized anxiety disorder (GAD) (no significant response)66 ...
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Classics in Chemical Neuroscience: Memantine Shahrina Alam,† Kaelyn Skye Lingenfelter,† Aaron M. Bender,† and Craig W. Lindsley*,†,‡,§ †

ACS Chem. Neurosci. 2017.8:1823-1829. Downloaded from pubs.acs.org by EASTERN KENTUCKY UNIV on 01/21/19. For personal use only.

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 (moderateaffinity, 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 among 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

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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 AD 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 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 © 2017 American Chemical Society

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 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, 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 coprescribe memantine with cholinesterase inhibitors for greater efficacy across the spectrum of AD stages, and in 2014, Namzaric (a combination 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 Received: July 13, 2017 Accepted: July 24, 2017 Published: July 24, 2017 1823

DOI: 10.1021/acschemneuro.7b00270 ACS Chem. Neurosci. 2017, 8, 1823−1829

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direct amination of 5 with tert-BuOH/CH3CN in H2SO4 provides 7, which is hydrolyzed (PEG-400/NaOH/130−135 °C) to the primary amine and converted to the HCl salt 4. 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.

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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 $4562, and the standard dosing regimen is 10 mg orally twice daily, although dosing regimens 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 $4334, 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 combination pill consisting of 28 mg of memantine and 10 mg of donepezil on December 23, 2014.30 From all variants combined, memantine sales in 2017 are estimated at just under 1 billion dollars, but sales reached approximately $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

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).

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.

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CHEMICAL PROPERTIES AND SYNTHESIS Memantine, 4 (CAS no. 41100-52-1, IUPAC name 3,5dimethyladamantan-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 C12H12N·HCl, and it is a highly water-soluble crystalline solid, with a melting point of 258 °C 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 inf ra). 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-3,5-dimethyl 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). 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 byproduct bromine vapor) with an overall yield of 75%. In this event,

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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 nonlinearity at lower doses, uncontrolled diet, and inaccurate IV dosing during clinical studies.32 Peak plasma levels for 4 are reached within 3−7 h, with food appearing to have no influence

Scheme 1. Original Synthesis of Memantine (4) from 1963

1824

DOI: 10.1021/acschemneuro.7b00270 ACS Chem. Neurosci. 2017, 8, 1823−1829

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ACS Chemical Neuroscience Scheme 2. Streamlined Process Route of Memantine (4)

Scheme 3. Recent Two-Step Route to Memantine (4)

on absorption rate. The terminal elimination half-life of 4 in man is between 60 and 80 h, 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) was noted. Also, no drug−drug interactions (DDIs) were found, and coadministration 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 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 steadystate concentration of 4 over a defined period of time and 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 Three major metabolites of 4 have been characterized and include an N-glucuronide conjugate (10), 6-hydroxymemantine (11), and 1-nitroso memantine (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 h, while the area under the plasma concentration−time curve from time zero to infinity (AUC0→∞) was found to be 1716−2498 μg·h/L (9.3−13.5 μmol·h/L). In older healthy volunteers (n = 22,

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.

mean age 57), similar mean Cmax (24 μg/L [0.13 μmol/L]), Tmax (6.6 h), and AUC0→∞ (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 Volunteersa

a

parameter

memantine

Tmax (h) Cmax (ng mL−1) AUC0→∞ (ng h mL−1) MRT (h) t1/2 (h)

6.69 ± 3.23 12.2 ± 2.5 989 ± 260 84.7 ± 13.2 60.5 ± 8.8

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 Due to the pioneering work of Lipton,37−40 Parsons,41−43 and others, it is clear that memantine (4) is unique, a panacea among NMDA receptor antagonists. Memantine alone has been shown to block excitotoxic cell death in a clinically acceptable manner by targeting only 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, voltagedependent NMDA receptor antagonist with moderate affinity and fast on−off kinetics with greater efficacy in more severe excitotoxic/disease scenarios.37 The NMDA receptor is one of 1825

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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 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 that 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 σ-1 receptor, and the 5HT3 receptor and to 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 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

three classes of ionotropic receptors (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

Figure 3. (A) Cartoon structure of the NMDA receptor highlighting the critical modulatory sites. (B) Structures of the coagonists glycine (13) with glutamate (14) or NMDA (15) and well characterized noncompetitive NMDA antagonists 16−18 with long “dwell” times and severe adverse events. Adapted from ref 37.

composed of different NR1 and NR2 subunits (NR3 subunits have recently been identified).46 For the channel to open, the obligatory coagonists 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. Overactivation 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 overactivation 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 they were competitive) and blocked both physiological/normal and pathological states of the

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

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 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 1826

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As a chemotype, amantadine (19) was the progenitor of 4 and was originally introduced in the 1960s as an antiviral (influenza) medication. Serendipitously, a lone patient on 19 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 (antidiabetics).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 (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 laboratories to develop 4 for AD in the United States, which was approved by the FDA in 2003 as Namenda. Importantly, this was the only noncholinergic medication for AD and the only one 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 was not 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 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 expanded across all stages of AD by the combination pill Namzaric. Without question, memantine is a classic in chemical neuroscience that

come close is neramexane (21), a pentamethyl aminocyclohexane (Figure 4), which binds at the memantine site with similar affinity and has advanced to clinical trials.52

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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, reduction in behavioral disturbances, improved global function assessments, and delayed 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 and comorbid depression and alcoholism (similarly effective to escitalopram with regards to drinking).64 Other clinical trials are being considered or are 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 eight double-blind placebo controlled dementia clinical trials alone, where ∼2000 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 MK801 of 3.1 in vitro and 5.4 in vivo. Overall, 4 has proven to be a safe and effective medication.32,41

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HISTORY AND IMPORTANCE IN NEUROSCIENCE As mentioned previously, memantine is a panacea among 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. 1827

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(15) Reisberg, B., Doody, R., Stoffler, A., Schmitt, F., Ferris, S., and Mobius, H. J. (2003) Memantine in moderate-to-severe Alzheimer’s disease. N. Engl. J. Med. 348, 1333−1341. (16) Forest Pharmaceuticals Inc. (2014) Namzaric (memantine hydrochloride extended-release and donepezil hydrochloride) capsules, for oral use: US prescribing information. http://www.fda.gov. (17) Greig, S. L. (2015) Memantine ER/Donepezil: A review in Alzheimer’s disease. CNS Drugs 29, 963−970. (18) Hardy, J., and Selkoe, D. J. (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297, 353−356. (19) Doig, A. J., Del Castillo-Frias, M. P., Berthoumieu, O., Tarus, B., Nasica-Labouze, J., Sterpone, F., Nguyen, P. H., Hooper, N. M., Faller, P., and Derreumaux, P. (2017) Why is research on amyloid-β failing to give new drugs for Alzheimer’s disease. ACS Chem. Neurosci. 8, 1435. (20) Limapichat, W., Yu, W. Y., Branigan, E., Lester, H. A., and Dougherty, D. A. (2013) Key binding interactions for memantine in the NMDA receptor. ACS Chem. Neurosci. 4, 255−260. (21) Wager, T. T., Hou, Y., Verhoest, P. R., and Villalobos, A. (2016) Central nervous system multiparameter optimization desirability: Application in drug discovery. ACS Chem. Neurosci. 7, 767−775. (22) Gerzon, K., Krumkalns, E. V., Brindle, R. L., Marshall, F. J., and Root, M. A. (1963) The adamantle group in medicinal agents. I. Hypoglycemic N-arylsulfonyl-N′-adamantylureas. J. Med. Chem. 6, 760−763. (23) Mills, J., and Krumkalns, E. V. (1968) U.S. Patent 3,391,142. (24) Scherin, A., Homburg, B., Petri, D., and Markobel, H. (1978) U.S. Patent 4,122,193. (25) Madhra, M. K., Sharma, M., and Khanduri, C. H. (2007) New synthetic approach to memantine hydrochloride starting form 1,3dimehtyl-adamantane. Org. Process Res. Dev. 11, 922−923. (26) Reddy, J. M., Prasad, G., Raju, V., Ravikumar, M., Himabindu, V., and Reddy, G. M. (2007) An improved synthesis of memantine hydrochloride: An anti-Alzheimer’s drug. Org. Process Res. Dev. 11, 268−269. (27) Zhu, Y., Li, X., Wang, X., Huang, X., Shen, T., Zhang, Y., Sun, X., Zou, M., Song, S., and Jiao, N. (2015) Silver-Catalyzed Decarboxylative Azidation of Aliphatic Carboxylic Acids. Org. Lett. 17, 4702− 4705. (28) Plosker, G. L. (2015) Memantine extended release (28 mg once daily): a review of its use in Alzheimer’s disease. Drugs 75, 887−897. (29) http://druginserts.com/lib/rx/meds/namenda-xr/. (30) http://www.namzaric.com. (31) https://www.drugs.com/availability/generic-namenda.html. (32) Tandon V. US Food and Drug Administration Center for Drug Evaluation and Research and approval package for application number 21-487. Clinical pharmacology and biopharmaceutics review: memantine [online]. Available from URL: https://www.accessdata.fda.gov/ drugsatfda_docs/nda/2003/21-487_namenda.cfm. (33) Schmitt, F., Ryan, M., and Cooper, G. (2007) A brief review of the pharmacological and therapeutic aspects of memantine in Alzheimer’s disease. Expert Opin. Drug Metab. Toxicol. 3, 135−141. (34) Freudenthaler, S., Meineke, I., Schreeb, K. H., Boakye, E., Gundert-Remy, U., and Gleiter, C. H. (1998) Influence of urine pH and urinary flow on the renal extraction of memantine. Br. J. Clin. Pharmacol. 46, 541−546. (35) Pan, R.-N., Chian, T.-Y., Kuo, B. P.-C., and Pao, L.-H. (2009) Determination of memantine in human plasma by LC−MS−MS: application to a pharmacokinetic study. Chromatographia 70, 783−788. (36) Mehta, D. C., Short, J. L., and Nicolazzo, J. A. (2013) Memantine transport across the mouse blood-brain barrier is mediated by cationic influx H+ antiporter. Mol. Pharmaceutics 10, 4491−4498. (37) Lipton, S. A. (2006) Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond. Nat. Rev. Drug Discovery 5, 160−170. (38) Lipton, S. A. (2004) Concepts: turning down, but not off. Nature 428, 473. (39) Chen, H.-S. V., and Lipton, S. A. (2005) Pharmacological implications of two distinct mechanisms of interaction of memantine

intrigues pharmacologists and medicinal chemists while benefiting patients.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Craig W. Lindsley: 0000-0003-0168-1445 Author Contributions

S.A., K.S.L., A.M.B., 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.

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ACKNOWLEDGMENTS 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.).

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

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REFERENCES

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