Skip to main content

Advertisement

SpringerLink
Log in

Improved cognition without adverse effects: novel M1 muscarinic potentiator compares favorably to donepezil and xanomeline in rhesus monkey

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

The standards of care for Alzheimer’s disease, acetylcholinesterase inhibitors such as donepezil (Aricept®), are dose-limited due to adverse side-effects. These adverse events lead to significant patient non-compliance, constraining the dose and magnitude of efficacy that can be achieved. Non-selective muscarinic receptor orthosteric agonists such as Xanomeline have been shown to be effective in treating symptoms as well, but were also poorly tolerated. Therefore, there is an unmet medical need for a symptomatic treatment that improves symptoms and is better tolerated.

Methods

We compared donepezil, xanomeline, and the novel selective muscarinic 1 receptor positive allosteric modulator PQCA in combination with donepezil in the object retrieval detour (ORD) cognition test in rhesus macaque. Gastrointestinal (GI) side effects (salivation and feces output) were then assessed with all compounds to determine therapeutic window.

Results

All three compounds significantly reduced a scopolamine-induced deficit in ORD. Consistent with what is observed clinically in patients, both donepezil and xanomeline produced significant GI effects in rhesus at doses equal to or less than a fivefold margin from the minimum effective dose that improves cognition. In stark contrast, PQCA produced no GI side effects when tested at the same dose range.

Conclusions

These data suggest M1 positive allosteric modulators have the potential to improve cognition in Alzheimer’s disease with a greater therapeutic margin than the current standard of care, addressing an important unmet medical need.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Atri A, Shaughnessy LW, Locascio JJ, Growdon JH (2008) Long-term course and effectiveness of combination therapy in Alzheimer disease. Alzheimer Dis Assoc Disord 22:209–221

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bartko SJ, Romberg C, White B, Wess J, Bussey TJ, Saksida LM (2011) Intact attentional processing but abnormal responding in M1 muscarinic receptor-deficient mice using an automated touchscreen method. Neuropharmacology 61:1366–1378

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bartus RT, Dean RL 3rd, Beer B, Lippa AS (1982) The cholinergic hypothesis of geriatric memory dysfunction. Science 217:408–414

    Article  CAS  PubMed  Google Scholar 

  • Beguin P, Beggah A, Cotecchia S, Geering K (1996) Adrenergic, dopaminergic, and muscarinic receptor stimulation leads to PKA phosphorylation of Na-K-ATPase. Am J Physiol 270:C131–C137

    CAS  PubMed  Google Scholar 

  • Birks J (2006) Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database Syst Rev CD005593

  • Birks J, Flicker L (2006) Donepezil for mild cognitive impairment. Cochrane Database Syst Rev CD006104

  • Birks J, Harvey RJ (2006) Donepezil for dementia due to Alzheimer’s disease. Cochrane Database Syst Rev CD001190

  • Bodick NC, Offen WW, Levey AI, Cutler NR, Gauthier SG, Satlin A, Shannon HE, Tollefson GD, Rasmussen K, Bymaster FP, Hurley DJ, Potter WZ, Paul SM (1997a) Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease. Arch Neurol 54:465–473

    Article  CAS  PubMed  Google Scholar 

  • Bodick NC, Offen WW, Shannon HE, Satterwhite J, Lucas R, van Lier R, Paul SM (1997b) The selective muscarinic agonist xanomeline improves both the cognitive deficits and behavioral symptoms of Alzheimer disease. Alzheimer Dis Assoc Disord 11(Suppl 4):S16–S22

    CAS  PubMed  Google Scholar 

  • Broks P, Preston GC, Traub M, Poppleton P, Ward C, Stahl SM (1988) Modelling dementia: effects of scopolamine on memory and attention. Neuropsychologia 26:685–700

    Article  CAS  PubMed  Google Scholar 

  • Cummings JL, Geldmacher D, Farlow M, Sabbagh M, Christensen D, Betz P (2013) High-dose donepezil (23 mg/day) for the treatment of moderate and severe Alzheimer’s disease: drug profile and clinical guidelines. CNS Neurosci Ther 19:294–301

    Article  CAS  PubMed  Google Scholar 

  • Delrieu J, Piau A, Caillaud C, Voisin T, Vellas B (2011) Managing cognitive dysfunction through the continuum of Alzheimer’s disease: role of pharmacotherapy. CNS Drugs 25:213–226

    Article  CAS  PubMed  Google Scholar 

  • Diamond A, Zola-Morgan S, Squire LR (1989) Successful performance by monkeys with lesions of the hippocampal formation on AB and object retrieval, two tasks that mark developmental changes in human infants. Behav Neurosci 103:526–537

    Article  CAS  PubMed  Google Scholar 

  • Drachman DA, Leavitt J (1974) Human memory and the cholinergic system. A relationship to aging? Arch Neurol 30:113–121

    Article  CAS  PubMed  Google Scholar 

  • Dronfield S, Egan K, Marsden CA, Green AR (2000) Comparison of donepezil-, tacrine-, rivastigmine- and metrifonate-induced central and peripheral cholinergically mediated responses in the rat. J Psychopharmacol 14:275–279

    Article  CAS  PubMed  Google Scholar 

  • Eglen RM (2005) Muscarinic receptor subtype pharmacology and physiology. Prog Med Chem 43:105–136

    Article  CAS  PubMed  Google Scholar 

  • Felder CC (1995) Muscarinic acetylcholine receptors: signal transduction through multiple effectors. FASEB J 9:619–625

    CAS  PubMed  Google Scholar 

  • Hatcher JP, Loudon JM, Hagan JJ, Clark MS (1998) Sabcomeline (SB-202026), a functionally selective M1 receptor partial agonist, reverses delay-induced deficits in the T-maze. Psychopharmacology (Berl) 138:275–282

    Article  CAS  Google Scholar 

  • Heinrich JN, Butera JA, Carrick T, Kramer A, Kowal D, Lock T, Marquis KL, Pausch MH, Popiolek M, Sun SC, Tseng E, Uveges AJ, Mayer SC (2009) Pharmacological comparison of muscarinic ligands: historical versus more recent muscarinic M1-preferring receptor agonists. Eur J Pharmacol 605:53–56

    Article  CAS  PubMed  Google Scholar 

  • Ihl R, Frolich L, Winblad B, Schneider L, Burns A, Moller HJ (2011) World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of Alzheimer’s disease and other dementias. World J Biol Psychiatry 12:2–32

    Article  PubMed  Google Scholar 

  • Iwanaga Y, Miyashita N, Morikawa K, Mizumoto A, Kondo Y, Itoh Z (1990) A novel water-soluble dopamine-2 antagonist with anticholinesterase activity in gastrointestinal motor activity. Comparison with domperidone and neostigmine. Gastroenterology 99:401–408

    CAS  PubMed  Google Scholar 

  • Jentsch JD, Taylor JR, Elsworth JD, Redmond DE Jr, Roth RH (1999a) Altered frontal cortical dopaminergic transmission in monkeys after subchronic phencyclidine exposure: involvement in frontostriatal cognitive deficits. Neuroscience 90:823–832

    Article  CAS  PubMed  Google Scholar 

  • Jentsch JD, Taylor JR, Redmond DE Jr, Elsworth JD, Youngren KD, Roth RH (1999b) Dopamine D4 receptor antagonist reversal of subchronic phencyclidine-induced object retrieval/detour deficits in monkeys. Psychopharmacology (Berl) 142:78–84

    Article  CAS  Google Scholar 

  • Knopman DS (2012) Donepezil 23 mg: an empty suit. Neurol Clin Pract 2:352–355

    Article  PubMed Central  PubMed  Google Scholar 

  • Kuduk SD, Chang RK, Di Marco CN, Pitts DR, Greshock TJ, Ma L, Wittmann M, Seager MA, Koeplinger KA, Thompson CD, Hartman GD, Bilodeau MT, Ray WJ (2011) Discovery of a selective allosteric M1 receptor modulator with suitable development properties based on a quinolizidinone carboxylic acid scaffold. J Med Chem 54:4773–4780

    Article  CAS  PubMed  Google Scholar 

  • Levey AI (1993) Immunological localization of m1-m5 muscarinic acetylcholine receptors in peripheral tissues and brain. Life Sci 52:441–448

    Article  CAS  PubMed  Google Scholar 

  • Liston DR, Nielsen JA, Villalobos A, Chapin D, Jones SB, Hubbard ST, Shalaby IA, Ramirez A, Nason D, White WF (2004) Pharmacology of selective acetylcholinesterase inhibitors: implications for use in Alzheimer’s disease. Eur J Pharmacol 486:9–17

    Article  CAS  PubMed  Google Scholar 

  • Lockhart IA, Mitchell SA, Kelly S (2009) Safety and tolerability of donepezil, rivastigmine and galantamine for patients with Alzheimer’s disease: systematic review of the ‘real-world’ evidence. Dement Geriatr Cogn Disord 28:389–403

    Article  CAS  PubMed  Google Scholar 

  • Marino MJ, Rouse ST, Levey AI, Potter LT, Conn PJ (1998) Activation of the genetically defined m1 muscarinic receptor potentiates N-methyl-D-aspartate (NMDA) receptor currents in hippocampal pyramidal cells. Proc Natl Acad Sci U S A 95:11465–11470

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Matsui M, Yamada S, Oki T, Manabe T, Taketo MM, Ehlert FJ (2004) Functional analysis of muscarinic acetylcholine receptors using knockout mice. Life Sci 75:2971–2981

    Article  CAS  PubMed  Google Scholar 

  • Mirza NR, Peters D, Sparks RG (2003) Xanomeline and the antipsychotic potential of muscarinic receptor subtype selective agonists. CNS Drug Rev 9:159–186

    Article  CAS  PubMed  Google Scholar 

  • Muller W, Petrozzino JJ, Griffith LC, Danho W, Connor JA (1992) Specific involvement of Ca(2+)-calmodulin kinase II in cholinergic modulation of neuronal responsiveness. J Neurophysiol 68:2264–2269

    CAS  PubMed  Google Scholar 

  • Nagahama K, Matsunaga Y, Kawachi M, Ito K, Tanaka T, Hori Y, Oka H, Takei M (2012) Acotiamide, a new orally active acetylcholinesterase inhibitor, stimulates gastrointestinal motor activity in conscious dogs. Neurogastroenterol Motil 24(566–74):e256

    Google Scholar 

  • Peralta EG, Ashkenazi A, Winslow JW, Ramachandran J, Capon DJ (1988) Differential regulation of PI hydrolysis and adenylyl cyclase by muscarinic receptor subtypes. Nature 334:434–437

    Article  CAS  PubMed  Google Scholar 

  • Rountree SD, Atri A, Lopez OL, Doody RS (2013) Effectiveness of antidementia drugs in delaying Alzheimer’s disease progression. Alzheimers Dement 9:338–345

    Article  PubMed  Google Scholar 

  • Schliebs R, Arendt T (2006) The significance of the cholinergic system in the brain during aging and in Alzheimer’s disease. J Neural Transm 113:1625–1644

    Article  CAS  PubMed  Google Scholar 

  • Schneider LS (2004) AD2000: donepezil in Alzheimer’s disease. Lancet 363:2100–2101

    Article  PubMed  Google Scholar 

  • Schneider LS (2012) Discontinuing donepezil or starting memantine for Alzheimer’s disease. N Engl J Med 366:957–959

    Article  CAS  PubMed  Google Scholar 

  • Sedman AJ, Bockbrader H, Schwarz RD (1995) Preclinical and phase 1 clinical characterization of CI-979/RU35926, a novel muscarinic agonist for the treatment of Alzheimer’s disease. Life Sci 56:877–882

    Article  CAS  PubMed  Google Scholar 

  • Shirey JK, Brady AE, Jones PJ, Davis AA, Bridges TM, Kennedy JP, Jadhav SB, Menon UN, Xiang Z, Watson ML, Christian EP, Doherty JJ, Quirk MC, Snyder DH, Lah JJ, Levey AI, Nicolle MM, Lindsley CW, Conn PJ (2009) A selective allosteric potentiator of the M1 muscarinic acetylcholine receptor increases activity of medial prefrontal cortical neurons and restores impairments in reversal learning. J Neurosci 29:14271–14286

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Sykes DA, Dowling MR, Charlton SJ (2009) Exploring the mechanism of agonist efficacy: a relationship between efficacy and agonist dissociation rate at the muscarinic M3 receptor. Mol Pharmacol 76:543–551

    Article  CAS  PubMed  Google Scholar 

  • Taylor JR, Elsworth JD, Roth RH, Sladek JR Jr, Redmond DE Jr (1990a) Cognitive and motor deficits in the acquisition of an object retrieval/detour task in MPTP-treated monkeys. Brain 113(Pt 3):617–637

    Article  PubMed  Google Scholar 

  • Taylor JR, Roth RH, Sladek JR Jr, Redmond DE Jr (1990b) Cognitive and motor deficits in the performance of an object retrieval task with a barrier-detour in monkeys (Cercopithecus aethiops sabaeus) treated with MPTP: long-term performance and effect of transparency of the barrier. Behav Neurosci 104:564–576

    Article  CAS  PubMed  Google Scholar 

  • Terry AV Jr, Buccafusco JJ (2003) The cholinergic hypothesis of age and Alzheimer’s disease-related cognitive deficits: recent challenges and their implications for novel drug development. J Pharmacol Exp Ther 306:821–827

    Article  CAS  PubMed  Google Scholar 

  • Thomas RL, Mistry R, Langmead CJ, Wood MD, Challiss RA (2008) G protein coupling and signaling pathway activation by m1 muscarinic acetylcholine receptor orthosteric and allosteric agonists. J Pharmacol Exp Ther 327:365–374

    Article  CAS  PubMed  Google Scholar 

  • Turon-Estrada A, Lopez-Pousa S, Gelada-Batlle E, Garre-Olmo J, Lozano-Gallego M, Hernandez-Ferrandiz M, Fajardo-Tibau C, Morante-Munoz V, Vilalta-Franch J (2003) Tolerance and adverse events of treatment with acetylcholinesterase inhibitors in a clinical sample of patients with very slight and mild Alzheimer s disease over a six-month period. Rev Neurol 36:421–424

    CAS  PubMed  Google Scholar 

  • Uslaner JM, Eddins D, Puri V, Cannon CE, Sutcliffe J, Chew CS, Pearson M, Vivian JA, Chang RK, Ray WJ, Kuduk SD, Wittmann M (2013) The muscarinic M1 receptor positive allosteric modulator PQCA improves cognitive measures in rat, cynomolgus macaque, and rhesus macaque. Psychopharmacology (Berl) 225:21–30

    Article  CAS  Google Scholar 

  • Veroff AE, Bodick NC, Offen WW, Sramek JJ, Cutler NR (1998) Efficacy of xanomeline in Alzheimer disease: cognitive improvement measured using the computerized neuropsychological test battery (CNTB). Alzheimer Dis Assoc Disord 12:304–312

    Article  CAS  PubMed  Google Scholar 

  • Watson J, Brough S, Coldwell MC, Gager T, Ho M, Hunter AJ, Jerman J, Middlemiss DN, Riley GJ, Brown AM (1998) Functional effects of the muscarinic receptor agonist, xanomeline, at 5-HT1 and 5-HT2 receptors. Br J Pharmacol 125:1413–1420

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wess J (2004) Muscarinic acetylcholine receptor knockout mice: novel phenotypes and clinical implications. Annu Rev Pharmacol Toxicol 44:423–450

    Article  CAS  PubMed  Google Scholar 

  • Wienrich M, Meier D, Ensinger HA, Gaida W, Raschig A, Walland A, Hammer R (2001) Pharmacodynamic profile of the M1 agonist talsaclidine in animals and man. Life Sci 68:2593–2600

    Article  CAS  PubMed  Google Scholar 

  • Wilkinson LS, Dias R, Thomas KL, Augood SJ, Everitt BJ, Robbins TW, Roberts AC (1997) Contrasting effects of excitotoxic lesions of the prefrontal cortex on the behavioural response to D-amphetamine and presynaptic and postsynaptic measures of striatal dopamine function in monkeys. Neuroscience 80:717–730

    Article  CAS  PubMed  Google Scholar 

  • Wood MD, Murkitt KL, Ho M, Watson JM, Brown F, Hunter AJ, Middlemiss DN (1999) Functional comparison of muscarinic partial agonists at muscarinic receptor subtypes hM1, hM2, hM3, hM4 and hM5 using microphysiometry. Br J Pharmacol 126:1620–1624

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Funding

All work was funded by Merck & Co., Inc.

Conflict of interest

All authors are currently employed at Merck & Co., Inc. or were employed at Merck and Co., Inc. at the time of their contributions.

Author information

Author notes

  1. Joshua D. Vardigan, Christopher E. Cannon, Vanita Puri, Mandy Dancho, AmyJo Koser, Marion Wittmann, Scott D. Kuduk, John J. Renger & Jason M. Uslaner

    Present address: Merck & Co., Inc., WP44E-200 770 Sumneytown Pike, West Point, PA, 19486, USA

Authors and Affiliations

    Authors
    1. Joshua D. Vardigan
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Christopher E. Cannon
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Vanita Puri
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Mandy Dancho
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. AmyJo Koser
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Marion Wittmann
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Scott D. Kuduk
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. John J. Renger
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Jason M. Uslaner
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Jason M. Uslaner.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Vardigan, J.D., Cannon, C.E., Puri, V. et al. Improved cognition without adverse effects: novel M1 muscarinic potentiator compares favorably to donepezil and xanomeline in rhesus monkey. Psychopharmacology 232, 1859–1866 (2015). https://doi.org/10.1007/s00213-014-3813-x

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s00213-014-3813-x

    Keywords

    Search

    Navigation