Clozapine, atypical antipsychotics, and the benefits of fast-off D2 dopamine receptor antagonism.

Naunyn-Schmiedeberg's Archives of Pharmacology
Georges VauquelinPhilip Seeman

Abstract

Drug-receptor interactions are traditionally quantified in terms of affinity and efficacy, but there is increasing awareness that the drug-on-receptor residence time also affects clinical performance. While most interest has hitherto been focused on slow-dissociating drugs, D(2) dopamine receptor antagonists show less extrapyramidal side effects but still have excellent antipsychotic activity when they dissociate swiftly. Fast dissociation of clozapine, the prototype of the "atypical antipsychotics", has been evidenced by distinct radioligand binding approaches both on cell membranes and intact cells. The surmountable nature of clozapine in functional assays with fast-emerging responses like calcium transients is confirmatory. Potential advantages and pitfalls of the hitherto used techniques are discussed, and recommendations are given to obtain more precise dissociation rates for such drugs. Surmountable antagonism is necessary to allow sufficient D(2) receptor stimulation by endogenous dopamine in the striatum. Simulations are presented to find out whether this can be achieved during sub-second bursts in dopamine concentration or rather during much slower, activity-related increases thereof. While the antagonist's dissociatio...Continue Reading

References

Jan 11, 1979·Nature·J W Kebabian, D B Calne
Mar 11, 1977·European Journal of Clinical Pharmacology·J Idänpään-HeikkiläI P Palva
Nov 1, 1975·Proceedings of the National Academy of Sciences of the United States of America·P SeemanK Wong
Nov 1, 1991·The American Journal of Psychiatry·K L DavisM Davidson
Aug 15, 1991·Biological Psychiatry·J G CsernanskyW O Faustman
Oct 1, 1989·Trends in Neurosciences·R L AlbinJ B Penney
Jan 1, 1989·Psychopharmacology·H Hippius
Jan 1, 1987·Psychopharmacology·J A LiebermanJ Alvir
Oct 11, 1988·European Journal of Pharmacology·E MellerM Goldstein
Jul 1, 1986·British Journal of Pharmacology·P Leff, G R Martin
Jan 1, 1988·Annals of the New York Academy of Sciences·G J MogensonC Y Yim
Aug 1, 1984·Proceedings of the National Academy of Sciences of the United States of America·Y SeverneG Vauquelin
Dec 22, 1983·Proceedings of the Royal Society of London. Series B, Containing Papers of a Biological Character·J W Black, P Leff
Jan 1, 1993·Journal of Neural Transmission. General Section·C L Nilsson, E Eriksson
Mar 1, 1994·The European Respiratory Journal·G P AndersonK F Rabe
May 10, 1994·Proceedings of the National Academy of Sciences of the United States of America·M S Lidow, P S Goldman-Rakic

❮ Previous
Next ❯

Citations

Nov 7, 2012·Naunyn-Schmiedeberg's Archives of Pharmacology·Gerhard GrossKarla U Drescher
Nov 28, 2013·Pharmacogenomics·Amy C C Kao, Daniel J Müller
Oct 21, 2015·Expert Opinion on Drug Discovery·Wilhelmus E A de WitteElizabeth C M de Lange
Dec 19, 2015·Nature Reviews. Drug Discovery·Robert A Copeland
Dec 23, 2015·Journal of Chemical Information and Modeling·Trayder ThomasDavid K Chalmers
Mar 5, 2013·Drug Discovery Today·Albert C PanDavid E Shaw
Aug 1, 2015·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Daniela VitucciAlessandro Usiello
Jan 3, 2016·Drug Discovery Today. Technologies·Georges VauquelinDavid C Swinney
Oct 28, 2015·ChemMedChem·Dong GuoAdriaan P IJzerman
Feb 20, 2014·Medicinal Research Reviews·Dong GuoLaura H Heitman
Apr 22, 2015·Progress in Neuro-psychopharmacology & Biological Psychiatry·Thais Emanoelle T PompeuFrançois Noël
Jun 11, 2015·Journal of Clinical Psychopharmacology·Nahla Mahgoub
May 26, 2015·Nature Chemical Biology·J Michael BradshawJack Taunton
Mar 19, 2015·Bioorganic & Medicinal Chemistry Letters·Kevin P CusackAnil Vasudevan
Oct 1, 2013·The International Journal of Neuropsychopharmacology·Kristoffer SahlholmPeter Århem
May 3, 2016·British Journal of Clinical Pharmacology·Georges Vauquelin
Apr 1, 2017·Future Medicinal Chemistry·Giuseppe Deganutti, Stefano Moro
Nov 17, 2017·Journal of Biomolecular NMR·Pablo Trigo-MouriñoDonghan Lee
Jul 27, 2018·Journal of Child and Adolescent Psychopharmacology·Przemysław M WaszakAlicja Kubanek
May 20, 2018·Journal of Pharmacokinetics and Pharmacodynamics·Wilhelmus E A de WitteElizabeth C M de Lange
Mar 3, 2020·Biomedit︠s︡inskai︠a︡ khimii︠a︡·D V Borisov, A V Veselovsky
Jul 26, 2017·Therapeutic Advances in Psychopharmacology·Judith J G RathDick Mul
Aug 23, 2018·Scientific Reports·Annika FrankHolger Stark
May 26, 2018·Therapeutic Advances in Drug Safety·Domenico De BerardisMassimo Di Giannantonio
Dec 16, 2020·Future Medicinal Chemistry·Joshua W ConnerNicholas A Veldhuis
Jun 5, 2021·RSC Medicinal Chemistry·Doris A SchuetzGerhard F Ecker
Jul 31, 2021·World Journal of Psychiatry·Mary V Seeman

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antipsychotic Drugs

Antipsychotic drugs are a class of medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia and bipolar disorder. Discover the latest research on antipsychotic drugs here

Basal Ganglia

Basal Ganglia are a group of subcortical nuclei in the brain associated with control of voluntary motor movements, procedural and habit learning, emotion, and cognition. Here is the latest research.