Clozapine, a Fast-Off-D2 Antipsychotic

Abstract

Ever since clozapine was first synthesized and tested, it showed the unique property of having antipsychotic action but no Parkinson-like motor side effects. The antipsychotic basis of clozapine is to transiently occupy dopamine D2 receptors in the human striatum, in contrast to haloperidol and chlorpromazine, which have a prolonged occupation of D2 receptors. The chemical structure of clozapine facilitates a relatively rapid dissociation from D2 receptors. After short-term occupation of D2 receptors, peak neural activity raises synaptic dopamine, which then displaces clozapine. While clozapine also occupies other types of receptors, they may not have a significant role in preventing parkinsonism. Clozapine's transient occupation of D2 receptors permits patients to move easily and comfortably.

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

“…Indeed the D 2 /5-HT 2A K i ratios obtained with LASSBio-579 and LQFM 037 in vitro (0.056 and 0.064, respectively) were about 100 times lower than with clozapine (6.5), according to previous data (Gomes et al, 2013). Furthermore, there are many exceptions to this concept of 5-HT 2A /D 2 relative selectivity for explaining atypicality (Seeman, 2014) as amisulpride, for example, is considered as a very selective antagonist of the D 2 -D 3 receptors lacking affinity for the 5-HT 2A receptors (Natesan et al, 2008). On the other hand, we cannot rule out a contribution of 5-HT 2A antagonism in vivo, for two reasons: 1.…”

“…In these experiments, clozapine, the more efficacious atypical antipsychotic, dissociated much more rapidly (k off about 80 times higher) than haloperidol, used here as reference typical antipsychotic. Although such low dissociation has been confirmed in recent works, especially for clozapine, quetiapine and olanzapine (Seeman, 2014;Vauquelin et al, 2012), not all published studies support the "fast-off" theory of atypicality. Sahlholm et al (2014), for instance, reported that recovery from clozapine and amisulpride antagonism was less than two fold faster than from chlorpromazine in a functional assay characterized by the presence of continuous buffer flow and of dopamine competition, supposed to prevent antagonist rebinding that can occur in binding dissociation studies (Vauquelin et al, 2012).…”

“…This concept was initially introduced to point out the advantages of long residence time with respect to duration of effect and target selectivity. On the contrary, in accordance with the "fast-off" theory of atypical antipsychotic action, a loose binding to the D 2 receptor would be beneficial thanks to a rapid dissociation from the receptor and a lower propensity to induce on-target toxicity such as EPS (Guo et al, 2013;Seeman, 2014). In the case of antipsychotics, a correlation was revealed between high affinity and in vitro low-dissociation rate (direct correlation between K i and k off ) for a series of drugs (Kapur and Seeman, 2000).…”

An update of safety of clinically used atypical antipsychotics

“…Moreover, clozapine is characterized by a rapid dissociation from D 2 receptors (the "fast off" phenomenon), that accounts for a more robust AP effect and lower propensity to cause EPS and HP [63]. Moreover, clozapine has an affinity to several other receptors, including serotonergic 5-HT 1A /5-HT 1C /5-HT 2A /5-HT 2C /5-HT 3 /5-HT 6 /5-HT 7 , adrenergic α1-/α2, histaminergic H 1 /H 3 /H 4 and muscarinic M 1 /M 5 receptors [64].…”