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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

Burstein, E. S. ; Ma, J. ; Wong, S. ; Gao, Y. ; Pham, E. ; Knapp, A. E. ; Nash, N. R. ; Olsson, R. LU orcid ; Davis, R. E. and Hacksell, U. , et al. (2005) In Journal of Pharmacology and Experimental Therapeutics 315(3). p.1278-1287
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 Gαo induces constitutive activity in the human D 2-like receptors (D2, D3, and D4). A large collection of typical and atypical antipsychotics was profiled for activity at these... (More)

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 Gαo induces constitutive activity in the human D 2-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 D 2 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.

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publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Pharmacology and Experimental Therapeutics
volume
315
issue
3
pages
1278 - 1287
publisher
American Society for Pharmacology and Experimental Therapeutics
external identifiers
  • scopus:27744476275
  • pmid:16135699
ISSN
0022-3565
DOI
10.1124/jpet.105.092155
language
English
LU publication?
no
id
042d6cfc-54c8-4526-b049-d6eda5852de8
date added to LUP
2019-10-02 10:33:07
date last changed
2024-06-27 06:40:35
@article{042d6cfc-54c8-4526-b049-d6eda5852de8,
  abstract     = {{<p>Drugs that antagonize D<sub>2</sub>-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 Gα<sub>o</sub> induces constitutive activity in the human D <sub>2</sub>-like receptors (D<sub>2</sub>, D<sub>3</sub>, and D<sub>4</sub>). A large collection of typical and atypical antipsychotics was profiled for activity at these receptors. Virtually all were D<sub>2</sub> and D<sub>3</sub> inverse agonists, whereas none was D<sub>4</sub> inverse agonist, although many were potent D<sub>4</sub> antagonists. The inverse agonist activity of haloperidol at D<sub>2</sub> and D<sub>3</sub> 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 D <sub>2</sub> and D<sub>3</sub> 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.</p>}},
  author       = {{Burstein, E. S. and Ma, J. and Wong, S. and Gao, Y. and Pham, E. and Knapp, A. E. and Nash, N. R. and Olsson, R. and Davis, R. E. and Hacksell, U. and Weiner, D. M. and Brann, M. R.}},
  issn         = {{0022-3565}},
  language     = {{eng}},
  month        = {{12}},
  number       = {{3}},
  pages        = {{1278--1287}},
  publisher    = {{American Society for Pharmacology and Experimental Therapeutics}},
  series       = {{Journal of Pharmacology and Experimental Therapeutics}},
  title        = {{Intrinsic efficacy of antipsychotics at human D<sub>2</sub>, D<sub>3</sub>, and D<sub>4</sub> dopamine receptors : Identification of the clozapine metabolite N-desmethylclozapine as a D<sub>2</sub>/D<sub>3</sub> partial agonist}},
  url          = {{http://dx.doi.org/10.1124/jpet.105.092155}},
  doi          = {{10.1124/jpet.105.092155}},
  volume       = {{315}},
  year         = {{2005}},
}