title: Pharmacology of JNJ-37822681, a specific and fast-dissociating D2 antagonist for the treatment of schizophrenia.
abstract: All marketed antipsychotics act by blocking dopamine D(2) receptors. Fast dissociation from D(2) receptors may be one of the elements contributing to the lower incidence of extrapyramidal symptoms (EPS) exhibited by newer antipsychotics. Therefore, we screened for specific D(2) receptor blockers with a fast rate of dissociation. Radioligand binding experiments identified N-[1-(3,4-difluorobenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine (JNJ-37822681) as a fast-dissociating D(2) ligand. Its D(2) receptor specificity was high compared with atypical antipsychotics, with little activity at receptors associated with unwanted effects [α(1), α(2), H(1), muscarinic, and 5-hydroxytryptamine (5-HT) type 2C] and for receptors that may interfere with the effects of D(2) antagonism (D(1), D(3), and 5-HT(2A)). JNJ-37822681 occupied D(2) receptors in rat brain at relatively low doses (ED(50) 0.39 mg/kg) and was effective in animal models of psychosis (e.g., inhibition of apomorphine-induced stereotypy or D-amphetamine/phencyclidine-induced hyperlocomotion). Prolactin levels increased from an ED(50) (0.17 mg/kg, peripheral D(2) receptors) close to the ED(50) required for apomorphine antagonism (0.19 mg/kg, central D(2) receptors), suggesting excellent brain disposition and minimal prolactin release at therapeutic doses. JNJ-37822681 induced catalepsy and inhibited avoidance behavior, but with a specificity margin relative to apomorphine antagonism that was larger than that obtained for haloperidol and similar to that obtained for olanzapine. This larger specificity margin (compared with haloperidol) may reflect lower EPS liability and less behavioral suppression after JNJ-37822681. JNJ-37822681 is a novel, potent, specific, centrally active, fast-dissociating D(2) antagonist with optimal brain disposition, and it is the first compound that allows the evaluation of the potential value of fast D(2) antagonism for the treatment of schizophrenia and bipolar disorder.
authors.affiliation: Neuroscience, Janssen Research and Development, Janssen Pharmaceutica NV, Beerse, Belgium. xlangloi@its.jnj.com
authors.forename: Xavier
authors.initials: X
authors.lastname: Langlois
authors.forename: Anton
authors.initials: A
authors.lastname: Megens
authors.forename: Hilde
authors.initials: H
authors.lastname: Lavreysen
authors.forename: John
authors.initials: J
authors.lastname: Atack
authors.forename: Miroslav
authors.initials: M
authors.lastname: Cik
authors.forename: Paula
authors.initials: P
authors.lastname: te Riele
authors.forename: Luc
authors.initials: L
authors.lastname: Peeters
authors.forename: Ria
authors.initials: R
authors.lastname: Wouters
authors.forename: Jef
authors.initials: J
authors.lastname: Vermeire
authors.forename: Herman
authors.initials: H
authors.lastname: Hendrickx
authors.forename: Gregor
authors.initials: G
authors.lastname: Macdonald
authors.forename: Marcel
authors.initials: M
authors.lastname: De Bruyn
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001058:Apomorphine / Q000037:antagonists & inhibitors / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D001569:Benzodiazepines / Q000009:adverse effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016466:CHO Cells; D002375:Catalepsy / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D002478:Cells, Cultured; D006224:Cricetinae; D018492:Dopamine Antagonists / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D005260:Female; D006220:Haloperidol / Q000009:adverse effects / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008124:Locomotion / Q000187:drug effects; D008297:Male; D000077152:Olanzapine; D010880:Piperidines / Q000494:pharmacology*; D011388:Prolactin / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D008024:Ligands; C576398:N-(1-(3,4-difluorobenzyl)piperidin-4-yl)-6-(trifluoromethyl)pyridazin-3-amine; D010880:Piperidines; D011724:Pyridazines; D017448:Receptors, Dopamine D2; D001569:Benzodiazepines; D012701:Serotonin; D011388:Prolactin; D006220:Haloperidol; D001058:Apomorphine; D000077152:Olanzapine