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.

Rasd2 Modulates Prefronto-Striatal Phenotypes in Humans and ‘Schizophrenia-Like Behaviors’ in Mice

“…On the other hand, the finding that Clz prevented the PPI deficits seen in PCP-treated KO mice is consistent with the pharmacodynamic profile of Clz, which binds to D2R and blocks 5HT 2A receptors with high affinity, thus preventing further dopamine release within the striatum (Seeman, 2014;Vauquelin et al, 2012). However, as Clz is a broad-spectrum ligand (Wenthur et al, 2014), at present its specific mechanism of action in Rasd2 KOs is still unclear.…”

Partial agonism and fast dissociation of LASSBio-579 at dopamine D2 receptor

“…In fact, the mechanism supporting their atypical profile has not been unveiled, even for clozapine, and could have different backgrounds as suggested by several concepts that have been proposed: dual antagonism at 5-HT 2A and D 2 receptors (Meltzer, 1989), selective blockade of D 4 receptors (clozapine), partial agonism at 5-HT 1A receptors (Newman-Tancredi and Kleven, 2011), rapid dissociation (Seeman, 2002) and/or partial agonism (Strange, 2008) at D 2 receptors and inhibition of glycogen synthase kinase-3 (Beaulieu et al, 2009). Focusing on the D 2 receptor, the "fast-off" theory proposes that atypical drugs are loosely bound and rapidly released from D 2 receptors in the synapse explaining their lower propensity to induce EPS and hyperprolactinemia (Ginovart and Kapur, 2012;Kapur and Seeman, 2000;Seeman, 2002;Vauquelin et al, 2012). Another property that could explain the atypicality of some antipsychotic is a partial agonism at the D 2 receptor.…”

Cell membranes… and how long drugs may exert beneficial pharmacological activity in vivo

“…However, a long residence time may also trigger 'mechanism'-based toxicity, such as the emergence of the extrapyramidal side effects associated with antipsychotic agents such as haloperidol [10]. These side effects are greatly reduced with fast-dissociating 'atypical' antipsychotic agents such as clozapine because their D 2 receptor blockade can be overcome/surmounted effectively by brief increases in the dopamine concentration in the striatum [11].There is increasing concern that integrating the 'residence time' concept in the drug discovery cascade may have only limited translatability into clinical efficacy [12,13]. In support of this view, it has been suggested [14] that many therapeutic drugs have slower elimination than dissociation rates, indicating that the PK component prevails.…”