title: Intrinsic efficacy of antipsychotics at human D2, D3, and D4 dopamine receptors: identification of the clozapine metabolite N-desmethylclozapine as a D2/D3 partial agonist.
abstract: Drugs that antagonize D2-like receptors are effective antipsychotics, but the debilitating movement disorder side effects associated with these drugs cannot be dissociated from dopamine receptor blockade. The "atypical" antipsychotics have a lower propensity to cause extrapyramidal symptoms (EPS), but the molecular basis for this is not fully understood nor is the impact of inverse agonism upon their clinical properties. Using a cell-based functional assay, we demonstrate that overexpression of Galphao induces constitutive activity in the human D2-like receptors (D2, D3, and D4). A large collection of typical and atypical antipsychotics was profiled for activity at these receptors. Virtually all were D2 and D3 inverse agonists, whereas none was D4 inverse agonist, although many were potent D4 antagonists. The inverse agonist activity of haloperidol at D2 and D3 receptors could be reversed by mesoridazine demonstrating that there were significant differences in the degrees of inverse agonism among the compounds tested. Aripiprazole and the principle active metabolite of clozapine NDMC [8-chloro-11-(1-piperazinyl)-5H-dibenzo [b,e] [1,4] diazepine] were identified as partial agonists at D2 and D3 receptors, although clozapine itself was an inverse agonist at these receptors. NDMC-induced functional responses could be reversed by clozapine. It is proposed that the low incidence of EPS associated with clozapine and aripiprazole used may be due, in part, to these partial agonist properties of NDMC and aripiprazole and that bypassing clozapine blockade through direct administration of NDMC to patients may provide superior antipsychotic efficacy.
authors.affiliation: ACADIA Pharmaceuticals, 3911 Sorrento Valley Blvd., San Diego, CA 92121, USA. eburstein@acadia-pharm.com
authors.forename: E S
authors.initials: ES
authors.lastname: Burstein
authors.forename: J
authors.initials: J
authors.lastname: Ma
authors.forename: S
authors.initials: S
authors.lastname: Wong
authors.forename: Y
authors.initials: Y
authors.lastname: Gao
authors.forename: E
authors.initials: E
authors.lastname: Pham
authors.forename: A E
authors.initials: AE
authors.lastname: Knapp
authors.forename: N R
authors.initials: NR
authors.lastname: Nash
authors.forename: R
authors.initials: R
authors.lastname: Olsson
authors.forename: R E
authors.initials: RE
authors.lastname: Davis
authors.forename: U
authors.initials: U
authors.lastname: Hacksell
authors.forename: D M
authors.initials: DM
authors.lastname: Weiner
authors.forename: M R
authors.initials: MR
authors.lastname: Brann
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000378:metabolism*; D003024:Clozapine / Q000378:metabolism*; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D010479:Pergolide / Q000494:pharmacology; D010957:Plasmids; D020710:RGS Proteins / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D050637:Receptors, Dopamine D3 / Q000819:agonists*; D050638:Receptors, Dopamine D4 / Q000378:metabolism*; D014162:Transfection
chemical_list: D014150:Antipsychotic Agents; D020710:RGS Proteins; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C488188:Rgs1 protein, mouse; D050638:Receptors, Dopamine D4; D010479:Pergolide; D003024:Clozapine; D006220:Haloperidol