Typical and atypical antipsychotics do not differ markedly in their reversibility of antagonism of the dopamine D2 receptor.
It has been suggested that the favorable side-effect profiles of atypical antipsychotics (e.g. clozapine and amisulpride) are related to their ∼100-fold faster dissociation from dopamine D2 receptors (D2R) compared with typical antipsychotics (e.g. haloperidol and chlorpromazine). Fast dissociation would entail rapidly reversible antagonism; however, this has not been thoroughly studied using functional assays. We compared the reversibilities of D2R antagonism by 17 compounds using an electrophysiological method to measure dopamine-evoked potassium channel activation via D2R. Varying rates and amplitudes of D2R response recovery were observed following antagonist removal. Whereas recovery rates differed 15-fold between atypical drugs, recovery from clozapine and amisulpride antagonism was, unexpectedly, less than twofold faster than from chlorpromazine. The recovery amplitude correlated with calculated water solubility and lipid/water distribution coefficients, suggesting variable drug partitioning into cell membranes. Our data do not support the notion that the rate of reversibility of D2R antagonism is what distinguishes atypical from typical antipsychotics.
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Kristoffer
K
Sahlholm
Daniel
D
Marcellino
Johanna
J
Nilsson
Sven Ove
SO
Ögren
Kjell
K
Fuxe
Peter
P
Århem
D000818:Animals; D014150:Antipsychotic Agents / Q000145:classification* / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D057927:Hydrophobic and Hydrophilic Interactions; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009865:Oocytes; D015221:Potassium Channels / Q000378:metabolism; D012995:Solubility; D014981:Xenopus
D014150:Antipsychotic Agents; D065127:Dopamine D2 Receptor Antagonists; D015221:Potassium Channels