title: Pharmacokinetics and central nervous system effects of the novel dopamine D2 receptor antagonist JNJ-37822681.
abstract: Using the rate of dissociation from the D(2) receptor as a means to screen novel compounds for antipsychotic drug candidates, the centrally acting and fast-dissociating selective dopamine D(2) receptor antagonist JNJ-37822681 was developed. In a blinded, placebo-controlled, randomized first-in-human study, JNJ-37822681 was administered orally to 27 healthy male volunteers at doses of 0.5, 2, 5, 10, 15 and 20 mg. Safety, pharmacokinetics and central nervous system effects were evaluated by measuring prolactin levels, eye movements, adaptive tracking, visual analogue scales, body sway, finger tapping and electroencephalography. JNJ-37822681 was well tolerated and somnolence was the most frequently reported adverse effect. Peak plasma concentrations increased more than proportional to dose, but increases in the area under curve (AUC) were dose-proportional. Prolactin elevations started at doses of 5 mg, whereas small decreases in adaptive tracking were demonstrated at 10 mg doses. At higher doses, JNJ-37822681 caused a small decrease in saccadic peak velocity, smooth pursuit, alertness, finger tapping and electroencephalography activity, and an increase in body sway. This effect profile is likely to be the result of the selectivity of JNJ-37822681 for the D(2) receptor, leading to strong D(2) receptor-mediated elevations in serum prolactin, but fewer effects on more complex central nervous system functions, which are likely to involve multiple neurotransmitters.
authors: Centre for Human Drug Research, Zernikedreef 10, Leiden, The Netherlands. etbeek@chdr.nl
authors: Erik T
authors: ET
authors: te Beek
authors: Matthijs
authors: M
authors: Moerland
authors: Peter
authors: P
authors: de Boer
authors: Luc
authors: L
authors: van Nueten
authors: Marieke L
authors: ML
authors: de Kam
authors: Jacobus
authors: J
authors: Burggraaf
authors: Adam F
authors: AF
authors: Cohen
authors: Joop M A
authors: JM
authors: van Gerven
mesh_terms: D000293:Adolescent; D000328:Adult; D001143:Arousal / Q000187:drug effects; D058256:Brain Waves / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects*; D018492:Dopamine Antagonists / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011187:Posture; D011388:Prolactin / Q000097:blood; D011698:Pursuit, Smooth / Q000187:drug effects; D011724:Pyridazines / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D012438:Saccades / Q000187:drug effects
chemical_list: D018492:Dopamine Antagonists; C576398:N-(1-(3,4-difluorobenzyl)piperidin-4-yl)-6-(trifluoromethyl)pyridazin-3-amine; D010880:Piperidines; D011724:Pyridazines; D011388:Prolactin