title: Clozapine, atypical antipsychotics, and the benefits of fast-off D2 dopamine receptor antagonism.
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 dissociation rate is important to distinguish between both mechanisms, this becomes much less so when contemplating time intervals between successive drug intakes, i.e., when pharmacokinetic considerations prevail. Attention is also drawn to the divergent residence times of hydrophobic antagonists like haloperidol when comparing radioligand binding data on cell membranes with those on intact cells and clinical data.
authors.affiliation: Department of Molecular and Biochemical Pharmacology, Vrije Universiteit Brussel, Pleinlaan 2, 1050, Brussels, Belgium. gvauquel@vub.ac.be
authors.forename: Georges
authors.initials: G
authors.lastname: Vauquelin
authors.forename: Sophie
authors.initials: S
authors.lastname: Bostoen
authors.forename: Patrick
authors.initials: P
authors.lastname: Vanderheyden
authors.forename: Philip
authors.initials: P
authors.lastname: Seeman
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D003024:Clozapine / Q000494:pharmacology* / Q000627:therapeutic use; D018492:Dopamine Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D065127:Dopamine D2 Receptor Antagonists; D006801:Humans; D011869:Radioligand Assay; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy
chemical_list: D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D017448:Receptors, Dopamine D2; D003024:Clozapine