title: alpha2C-Adrenoceptor blockade by clozapine and other antipsychotic drugs.
abstract: The noradrenergic system may play a role in antipsychotic modulation of schizophrenia symptoms. Therefore, the antagonistic potencies of the antipsychotics clozapine, chlorpromazine, risperidone, olanzapine, haloperidol, quetiapine, ziprasidone, iloperidone and aripiprazole were quantified using cell lines expressing the recombinant human alpha(2C)-adrenoceptor, alpha(2A)-adrenoceptor, or dopamine D(2L) receptor. The alpha(2)-adrenoceptor antagonists, yohimbine and idazoxan, were also tested. Alterations in cAMP were measured as changes in luminescence. In the alpha(2A)-adrenoceptor cell line, the agonist 5-bromo-6-(2-imidazolin-2-ylamino)quinoxaline (UK14,304) induced a concentration-dependent increase in luminescence. In cell lines expressing alpha(2C) and D(2L) receptors, agonists induced a concentration-dependent reduction in luminescence. Yohimbine and idazoxan were the most potent alpha(2A)-adrenoceptor antagonists, yohimbine and iloperidone were the most potent alpha(2C)-adrenoceptor antagonists, and haloperidol and olanzapine were the most potent dopamine D(2) receptor antagonists. Clozapine had the highest alpha(2C)/D(2) selectivity, and iloperidone the highest alpha(2C)/alpha(2A) ratio. It is hypothesised that alpha(2C)-adrenoceptor blockade contributes to improvement of cognitive function.
authors.affiliation: Novartis Pharma AG, Research Nervous System, Building WSJ-360-405, CH-4002 Basel, Switzerland. hans.kalkman@pharma.novartis.com
authors.forename: Hans O
authors.initials: HO
authors.lastname: Kalkman
authors.forename: Erika
authors.initials: E
authors.lastname: Loetscher
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D000068180:Aripiprazole; D001569:Benzodiazepines; D000068438:Brimonidine Tartrate; D016466:CHO Cells; D002746:Chlorpromazine / Q000494:pharmacology; D003024:Clozapine / Q000494:pharmacology*; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D003987:Dibenzothiazepines / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D000077152:Olanzapine; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D010890:Pirenzepine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000069348:Quetiapine Fumarate; D015363:Quinolones / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000502:physiology; D018967:Risperidone / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D014162:Transfection; D015016:Yohimbine / Q000494:pharmacology
chemical_list: C547768:ADRA2A protein, human; C547774:ADRA2C protein, human; D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D065127:Dopamine D2 Receptor Antagonists; D007555:Isoxazoles; D010879:Piperazines; D010880:Piperidines; D015363:Quinolones; D011810:Quinoxalines; D018341:Receptors, Adrenergic, alpha-2; D017448:Receptors, Dopamine D2; D013844:Thiazoles; C113776:dopamine D2L receptor; D001569:Benzodiazepines; D000069348:Quetiapine Fumarate; D015016:Yohimbine; D010890:Pirenzepine; D000068438:Brimonidine Tartrate; C092292:ziprasidone; D000068180:Aripiprazole; D000242:Cyclic AMP; D003024:Clozapine; D006220:Haloperidol; D018967:Risperidone; D000077152:Olanzapine; D002746:Chlorpromazine; C081732:iloperidone; D009638:Norepinephrine