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The highly efficacious actions of N-desmethylclozapine at muscarinic receptors are unique and not a common property of either typical or atypical antipsychotic drugs: is M1 agonism a pre-requisite for mimicking clozapine’s actions?

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Abstract

Rationale

Recent studies have suggested that the salutary actions of clozapine in schizophrenia may be due to selective activation of M1 muscarinic receptors by clozapine and/or its major active metabolite N-desmethylclozapine.

Objective

We systematically tested this hypothesis by screening a large number of psychoactive compounds, including many atypical antipsychotic drugs, for agonist activity at cloned, human M1, M3 and M5 muscarinic receptors.

Results

Only three of the 14 atypical antipsychotic drugs we tested were found to possess partial agonist actions at M1 muscarinic receptors (fluperlapine, JL13, clozapine). A few additional miscellaneous compounds had a modest degree of M1 agonist actions. Only carbachol and N-desmethylclozapine had appreciable M3 muscarinic agonism at M3 muscarinic receptors, although several were M5 partial agonists including MK-212, N-desmethylclozapine and xanomeline.

Conclusion

Although M1 muscarinic receptor-selective partial agonists have shown promise in some preclinical antipsychotic drug models, these studies indicate that it is unlikely that the salutary actions of clozapine and similar atypical antipsychotic drugs are mediated solely by M1 muscarinic receptor activation. It is possible, however, that the M1 agonism of N-desmethylclozapine contributes to the uniquely beneficial actions of clozapine. Thus, these results are consistent with the notion that a balanced degree of activity at multiple biogenic amine receptors, including M1 muscarinic agonism, is responsible for the uniquely beneficial actions of clozapine.

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References

  • Altar CA, Wasley AM, Neale RF, Stone GA (1986) Typical and atypical antipsychotic occupancy of D2 and S2 receptors: an autoradiographic analysis in rat brain. Brain Res Bull 16:517–525

    Article  CAS  PubMed  Google Scholar 

  • Ancellin N, Preisser L, Le Maout S, Barbado M, Creminon C, Corman B, Morel A (1999) Homologous and heterologous phosphorylation of the vasopressin V1a receptor. Cell Signal 11:743–751

    Article  CAS  PubMed  Google Scholar 

  • Bolden C, Cusack B, Richelson E (1992) Antagonism by antimuscarinic and neuroleptic compounds at the five cloned human muscarinic cholinergic receptors expressed in Chinese hamster ovary cells. J Pharmacol Exp Ther 260:576–580

    CAS  PubMed  Google Scholar 

  • Bymaster FP, Calligaro DO, Falcone JF, Marsh RD, Moore NA, Tye NC, Seeman P, Wong DT (1996) Radioreceptor binding profile of the atypical antipsychotic olanzapine. Neuropsychopharmacology 14:87–96

    Article  CAS  PubMed  Google Scholar 

  • Bymaster FP, Shannon HE, Rasmussen K, Delapp NW, Mitch CH, Ward JS, Calligaro DO, Ludvigsen TS, Sheardown MJ, Olesen PH, Swedberg MD, Sauerberg P, Fink-Jensen A (1998) Unexpected antipsychotic-like activity with the muscarinic receptor ligand (5R,6R)6-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1]octane. Eur J Pharmacol 356:109–119

    Article  CAS  PubMed  Google Scholar 

  • Bymaster FP, Felder C, Ahmed S, McKinzie D (2002) Muscarinic receptors as a target for drugs treating schizophrenia. Curr Drug Target CNS Neurol Disord 1:163–181

    CAS  Google Scholar 

  • Chavkin C, Sud S, Jin W, Steward J, Zjawiony JK, Siebert D, Toth BA, Hufeisen SJ, Roth BL (2004) Salvinorin A, an active component of the hallucinogenic sage salvia divinorum, is a highly efficacious kappa opioid receptor agonist: structural and functional considerations. J Pharmacol Exp Ther 368:1197–2003

    Google Scholar 

  • Crook JM, Tomaskovic-Crook E, Copolov DL, Dean B (2001) Low muscarinic receptor binding in prefrontal cortex from subjects with schizophrenia: a study of Brodmann’s areas 8, 9, 10, and 46 and the effects of neuroleptic drug treatment. Am J Psychiatry 158:918–925

    CAS  PubMed  Google Scholar 

  • de Paulis T (2001) M-100907 (Aventis). Curr Opin Invest Drugs 2:123–132

    PubMed  Google Scholar 

  • Dean B, McLeod M, Keriakous D, McKenzie J, Scarr E (2002) Decreased muscarinic1 receptors in the dorsolateral prefrontal cortex of subjects with schizophrenia. Mol Psychiatry 7:1083–1091

    Article  CAS  PubMed  Google Scholar 

  • Dean B, Bymaster FP, Scarr E (2003) Muscarinic receptors in schizophrenia. Curr Mol Med 3:419–426

    CAS  PubMed  Google Scholar 

  • Gewirtz GR, Gorman JM, Volavka J, Macaluso J, Gribkoff G, Taylor DP, Borison R (1994) BMY14802, a sigma receptor ligand for the treatment of schizophrenia. Neuropsychopharmacology 10:37–40

    CAS  PubMed  Google Scholar 

  • Harrison PJ, Owen MJ (2003) Genes for schizophrenia? Recent findings and their pathophysiological implications. Lancet 361:417–419

    Article  CAS  PubMed  Google Scholar 

  • Hodder P, Mull R, Cassaday J, Berry K, Strulovici B (2004) Miniaturization of intracellular calcium assays to 1536-well plate format using a fluorometric imaging plate reader. J Biomol Screen 9:417–426

    Article  CAS  PubMed  Google Scholar 

  • Janssen PA, Niemegeers CJ, Awouters F, Schellenkens KH, Megens AA, Meert TF (1988) Pharmacology of risperidone (R 64,766) a new antipsychotic with serotonin-S2 and dopamine-D2 antagonistic properties. J Pharmacol Exp Ther 244:685–693

    CAS  PubMed  Google Scholar 

  • Kahn RS, Siever L, Davidson M, Greenwald C, Moore C (1993) Haloperidol and clozapine treatment and their effect on M-chlorophenylpiperazine-mediated responses in schizophrenia: implications for the mechanism of action of clozapine. Psychopharmacology 112:S90–S94

    CAS  PubMed  Google Scholar 

  • Kane J, Honigfield G, Singer J, Meltzer HY, Group at CCS (1988) Clozapine for the treatment-resistant schizophrenic. Arch Gen Psychiatry 45:789–796

    CAS  PubMed  Google Scholar 

  • Karle J, Clemmesen L, Hansen L, Andersen M, Andersen J, Fensbo C, Sloth-Nielsen M, Skrumsager BK, Lublin H, Gerlach J (1995) NNC 01-0687, a selective dopamine D1 receptor antagonist, in the treatment of schizophrenia. Psychopharmacology 121:328–329

    CAS  PubMed  Google Scholar 

  • Kassack MU, Hofgen B, Lehmann J, Eckstein J, Quillan JM, Sadee W (2002) Functional screening of G protein coupled receptors by measuring intracellular calcium with a fluorescence microplate reader. J Biomol Screen 7:233–246

    Article  CAS  PubMed  Google Scholar 

  • Kenakin T (1997) Differences between natural and recombinant G protein-coupled receptor systems with varying receptor/G protein stoichiometry. Trends Pharmacol Sci 18:456–464

    Article  CAS  PubMed  Google Scholar 

  • Kohen R, Metcalf MA, Khan N, Druck T, Huebner K, Lachowicz JE, Meltzer HY, Sibley DR, Roth BL, Hamblin MW (1996) Cloning, characterization, and chromosomal localization of a human 5-HT6 serotonin receptor. J Neurochem 66:47–56

    CAS  PubMed  Google Scholar 

  • Kramer MS, Last B, Getson A, Reines SA (1997) The effects of a selective D4 dopamine receptor antagonist (L-745,870) in acutely psychotic inpatients with schizophrenia. D4 Dopamine Antagonist Group. Arch Gen Psychiatry 54:567

    CAS  PubMed  Google Scholar 

  • Kroeze WK, Sheffler DJ, Roth BL (2003) G-protein-coupled receptors at a glance. J Cell Sci 116:4867–4869

    Article  CAS  PubMed  Google Scholar 

  • Kuoppamaki M, Syvalahti E, Hietala J (1993) Clozapine and N-desmethylclozapine are potent 5-HT1C receptor antagonists. Eur J Pharmacol 245:179–182

    Article  CAS  PubMed  Google Scholar 

  • Lahti AC, Weiler M, Carlsson A, Tamminga CA (1998) Effects of the D3 and autoreceptor-preferring dopamine antagonist (+)-UH232 in schizophrenia. J Neural Transm 105:719–734

    Article  CAS  PubMed  Google Scholar 

  • Leucht S, Pitschel-Walz G, Engel RR, Kissling W (2002) Amisulpride, an unusual “atypical” antipsychotic: a meta-analysis of randomized controlled trials. Am J Psychiatry 159:180–190

    Article  PubMed  Google Scholar 

  • Leucht S, Wahlbeck K, Hamann J, Kissling W (2003) New generation antipsychotics versus low-potency conventional antipsychotics: a systematic review and meta-analysis. Lancet 361:1581–1589

    Article  CAS  PubMed  Google Scholar 

  • Liao DL, Hong CJ, Chen HM, Chen YE, Lee SM, Chang CY, Chen H, Tsai SJ (2003) Association of muscarinic m1 receptor genetic polymorphisms with psychiatric symptoms and cognitive function in schizophrenic patients. Neuropsychobiology 48:72–76

    Article  CAS  PubMed  Google Scholar 

  • Meltzer HY, McGurk SR (1999) The effects of clozapine, risperidone, and olanzapine on cognitive function in schizophrenia. Schizophr Bull 25:233–255

    CAS  PubMed  Google Scholar 

  • Meltzer HY, Matsubara S, Lee J-C (1989) Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values. J Pharmacol Exp Ther 251:238–246

    CAS  PubMed  Google Scholar 

  • Meltzer HY, Alphs L, Green AI, Altamura AC, Anand R, Bertoldi A, Bourgeois M, Chouinard G, Islam MZ, Kane J, Krishnan R, Lindenmayer JP, Potkin S (2003) Clozapine treatment for suicidality in schizophrenia: international suicide prevention trial (InterSePT). Arch Gen Psychiatry 60:82–91

    CAS  PubMed  Google Scholar 

  • Meltzer H, Arvantis L, Bauer D, Rein W, Group MS (2004) A placebo-controlled evaluation of four novel compounds for the treatment of schizophrenia and schizoaffective disorder. Arch Gen Psychiatry (in press)

  • Miller RJ, Hiley CR (1974) Anti-muscarinic properties of neuroleptics and drug-induced parkinsonism. Nature (London) 248:546–547

    Google Scholar 

  • Muller MJ, Grunder G, Wetzel H, Muller-Siecheneder F, Marx-Dannigkeit P, Benkert O (1999) Antipsychotic effects and tolerability of the sigma ligand EMD 57445 (panamesine) and its metabolites in acute schizophrenia: an open clinical trial. Psychiatry Res 89:275–280

    Article  CAS  PubMed  Google Scholar 

  • Newcomer JW, Faustman WO, Zipursky RB, Csernansky JG (1992) Zacopride in schizophrenia: a single-blind serotonin type 3 antagonist trial. Arch Gen Psychiatry 49:751–752

    CAS  PubMed  Google Scholar 

  • Newman-Tancredi A, Gavaudan S, Conte C, Chaput C, Touzard M, Verriele L, Audinot V, Millan MJ (1998) Agonist and antagonist actions of antipsychotic agents at 5-HT1A receptors: a [35S]GTPgammaS binding study. Eur J Pharmacol 355:245–256

    Article  CAS  PubMed  Google Scholar 

  • Olianas MC, Maullu C, Onali P (1999) Mixed agonist-antagonist properties of clozapine at different human cloned muscarinic receptor subtypes expressed in Chinese hamster ovary cells. Neuropsychopharmacology 20:263–270

    Article  CAS  PubMed  Google Scholar 

  • Pfeiffer CC, Jenney EH (1957) The inhibition of the conditioned response and the counteraction of schizophrenia by muscarinic stimulation of the brain. Ann N Y Acad Sci 66:753–764

    CAS  PubMed  Google Scholar 

  • Potkin SG, Shipley J, Bera R, Carreon D, Fallon J, Alva G, Keator D (2001) Clinical and PET Effects of M100907, a selective 5HT-2A receptor antagonist. Schizophr Res 49:242

    Google Scholar 

  • Poyurovsky M, Weizman A (1999) Lack of efficacy of the 5-HT3 receptor antagonist granisetron in the treatment of acute neuroleptic-induced akathisia. Int Clin Psychopharmacol 14:357–360

    CAS  PubMed  Google Scholar 

  • Raedler TJ, Knable MB, Jones DW, Urbina RA, Egan MF, Weinberger DR (2003a) Central muscarinic acetylcholine receptor availability in patients treated with clozapine. Neuropsychopharmacology 28:1531–1537

    Article  CAS  PubMed  Google Scholar 

  • Raedler TJ, Knable MB, Jones DW, Urbina RA, Gorey JG, Lee KS, Egan MF, Coppola R, Weinberger DR (2003b) In vivo determination of muscarinic acetylcholine receptor availability in schizophrenia. Am J Psychiatry 160:118–127

    Article  PubMed  Google Scholar 

  • Rasmussen T, Fink-Jensen A, Sauerberg P, Swedberg MD, Thomsen C, Sheardown MJ, Jeppesen L, Calligaro DO, DeLapp NW, Whitesitt C, Ward JS, Shannon HE, Bymaster FP (2001) The muscarinic receptor agonist BuTAC, a novel potential antipsychotic, does not impair learning and memory in mouse passive avoidance. Schizophr Res 49:193–201

    Article  CAS  PubMed  Google Scholar 

  • Rauser L, Savage JE, Meltzer HY, Roth BL (2001) Inverse agonist actions of typical and atypical antipsychotic drugs at the human 5-hydroxytryptamine(2C) receptor. J Pharmacol Exp Ther 299:83–89

    CAS  PubMed  Google Scholar 

  • Remington G, Kapur S (2001) SB-277011 GlaxoSmithKline. Curr Opin Invest Drugs 2:946–949

    CAS  Google Scholar 

  • Roth BL, Ciaranello RD, Meltzer HY (1992) Binding of typical and atypical antipsychotic agents to transiently expressed 5-HT1C receptors. J Pharmacol Exp Ther 260:1361–1365

    CAS  PubMed  Google Scholar 

  • Roth BL, Craigo SC, Choudhary MS, Uluer A, Monsma FJ Jr, Shen Y, Meltzer HY, Sibley DR (1994) Binding of typical and atypical antipsychotic agents to 5-hydroxytryptamine-6 and 5-hydroxytryptamine-7 receptors. J Pharmacol Exp Ther 268:1403–1410

    CAS  PubMed  Google Scholar 

  • Roth BL, Tandra S, Burgess LH, Sibley DR, Meltzer HY (1995) D4 dopamine receptor binding affinity does not distinguish between typical and atypical antipsychotic drugs. Psychopharmacology 120:365–368

    CAS  PubMed  Google Scholar 

  • Roth BL, Baner K, Westkaemper R, Siebert D, Rice KC, Steinberg S, Ernsberger P, Rothman RB (2002) Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist. Proc Natl Acad Sci USA 99:11934–11939

    Article  CAS  PubMed  Google Scholar 

  • Roth BL, Sheffler DJ, Potkin S (2003) Atypical antipsychotic drugs: unitary or multiple mechanisms for “atypicality”. Clin Neurosci Res 3:108–117

    Article  CAS  Google Scholar 

  • Roth BL, Kroeze WK, Sheffler DJ (2004) Magic bullets vs magic shotguns: why selectively non-selective drugs are better for treating schizophrenia and depression. Nat Rev Drug Discov 3:359–364

    Article  Google Scholar 

  • Rothman RB, Vu N, Partilla JS, Roth BL, Hufeisen SJ, Compton-Toth BA, Birkes J, Young R, Glennon RA (2003) In vitro characterization of ephedrine-related stereoisomers at biogenic amine transporters and the receptorome reveals selective actions as norepinephrine transporter substrates. J Pharmacol Exp Ther 307:138–145

    Article  CAS  PubMed  Google Scholar 

  • Schoemaker H, Claustre Y, Fage D, Rouquier L, Chergui K, Curet O, Oblin A, Gonon F, Carter C, Benavides J, Scatton B (1997) Neurochemical characteristics of amisulpride, an atypical dopamine D2/D3 receptor antagonist with both presynaptic and limbic selectivity. J Pharmacol Exp Ther 280:83–97

    CAS  PubMed  Google Scholar 

  • Seeger TF, Seymour PA, Schmidt AW, Zorn SH, Schulz DW, Lebel LA, McLean S, Guanowsky V, Howard HR, Lowe JA III et al. (1995) Ziprasidone (CP-88,059): a new antipsychotic with combined dopamine and serotonin receptor antagonist activity. J Pharmacol Exp Ther 275:101–113

    CAS  PubMed  Google Scholar 

  • Seibyl JP, Krystal JH, Pricer LH, Woods SW, Heninger GR, Charney DS (1989) 5-HT function in the biochemical and behavioral effects of MCPP in healthy subjects and schizophrenics. Soc Neurosci Abstr 15:1236

    Google Scholar 

  • Setola V, Hufeisen SJ, Grande-Allen KJ, Vesely I, Glennon RA, Blough B, Rothman RB, Roth BL (2003) 3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”) induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro. Mol Pharmacol 63:1223–1229

    Article  CAS  PubMed  Google Scholar 

  • Shannon HE, Rasmussen K, Bymaster FP, Hart JC, Peters SC, Swedberg MD, Jeppesen L, Sheardown MJ, Sauerberg P, Fink-Jensen A (2000) Xanomeline, an M(1)/M(4) preferring muscarinic cholinergic receptor agonist, produces antipsychotic-like activity in rats and mice. Schizophr Res 42:249–259

    Article  CAS  PubMed  Google Scholar 

  • Shapiro DA, Renock S, Arrington E, Chiodo LA, Liu LX, Sibley DR, Roth BL, Mailman R (2003) Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology. Neuropsychopharmacology 28:1400–1411

    Article  CAS  PubMed  Google Scholar 

  • Snyder S, Greenberg D, Yamamura HI (1974) Antischizophrenic drugs and brain cholinergic receptors. Affinity for muscarinic sites predicts extrapyramidal effects. Arch Gen Psychiatry 31:58–61

    CAS  PubMed  Google Scholar 

  • Sur C, Mallorga PJ, Wittmann M, Jacobson MA, Pascarella D, Williams JB, Brandish PE, Pettibone DJ, Scolnick EM, Conn PJ (2003) N-desmethylclozapine, an allosteric agonist at muscarinic 1 receptor, potentiates N-methyl-d-aspartate receptor activity. Proc Natl Acad Sci USA 100:13674–13679

    Article  CAS  PubMed  Google Scholar 

  • Tandon R (1999) Cholinergic aspects of schizophrenia. Br J Psychiatry Suppl 37:7–11

    PubMed  Google Scholar 

  • Tandon R, Greden JF (1987) Trihexyphenidyl treatment of negative schizophrenic symptoms. Acta Psychiatr Scand 76:732

    CAS  PubMed  Google Scholar 

  • Tandon R, Greden JF (1989) Cholinergic hyperactivity and negative schizophrenic symptoms. A model of cholinergic/dopaminergic interactions in schizophrenia. Arch Gen Psychiatry 46:745–753

    CAS  PubMed  Google Scholar 

  • Tuunainen A, Wahlbeck K, Gilbody S (2002) Newer atypical antipsychotic medication in comparison to clozapine: a systematic review of randomized trials. Schizophr Res 56:1–10

    Article  PubMed  Google Scholar 

  • Van Tol HH, Bunzow JR, Guan HC, Sunahara RK, Seeman P, Niznik HB, Civelli O (1991) Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature 350:610–614

    Article  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

    CAS  PubMed  Google Scholar 

  • Wetzel H, Szegedi A, Hain C, Wiesner J, Schlegel S, Benkert O (1995) Seroquel (ICI 204 636), a putative “atypical” antipsychotic, in schizophrenia with positive symptomatology: results of an open clinical trial and changes of neuroendocrinological and EEG parameters. Psychopharmacology 119:231–238

    CAS  PubMed  Google Scholar 

  • Zeng XP, Le F, Richelson E (1997) Muscarinic m4 receptor activation by some atypical antipsychotic drugs. Eur J Pharmacol 321:349–354

    Article  CAS  PubMed  Google Scholar 

  • Zorn SH, Jones SB, Ward KM, Liston DR (1994) Clozapine is a potent and selective muscarinic M4 receptor agonist. Eur J Pharmacol 269:R1–R2

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported in part by RO1MH57635, KO2MH01366 and the NIMH Psychoactive Drug Screening Program to B.L.R. M.A.D. was supported in part by a supplement to RO1MH57635.

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Correspondence to Bryan L. Roth.

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Davies, M.A., Compton-Toth, B.A., Hufeisen, S.J. et al. The highly efficacious actions of N-desmethylclozapine at muscarinic receptors are unique and not a common property of either typical or atypical antipsychotic drugs: is M1 agonism a pre-requisite for mimicking clozapine’s actions?. Psychopharmacology 178, 451–460 (2005). https://doi.org/10.1007/s00213-004-2017-1

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