title: L-745,870, a subtype selective dopamine D4 receptor antagonist, does not exhibit a neuroleptic-like profile in rodent behavioral tests.
abstract: This study examined the high-affinity, selective dopamine D4 receptor antagonist, L-745,870 (3-([4-(4-chlorophenyl)piperazin-1-yl]methyl)-1H-pyrrolo[2, 3-b]pyridine) in rodent behavioral models used to predict antipsychotic potential and side-effect liabilities in humans. In contrast to the classical neuroleptic, haloperidol, and the atypical neuroleptic, clozapine, L-745,870 failed to antagonize amphetamine-induced hyperactivity in mice or impair conditioned avoidance responding in the rat at doses selectively blocking D4 receptors. Furthermore, L-745,870 failed to reverse the deficit in prepulse inhibition of acoustic startle responding induced by the nonselective dopamine D2/3/4 receptor agonist apomorphine, an effect which was abolished in rats pretreated with the D2/3 receptor antagonist, raclopride (0.2 mg/kg s.c.). L-745,870 had no effect on apomorphine-induced stereotypy in the rat but did induce catalepsy in the mouse, albeit at a high dose of 100 mg/kg, which is likely to occupy dopamine D2 receptors in vivo. High doses also impaired motor performance; in rats L-745,870 significantly reduced spontaneous locomotor activity (minimum effective dose = 30 mg/kg) and in mice, L-745,870 reduced the time spent on a rotarod revolving at 15 rpm (minimum effective dose = 100 mg/kg). Altogether these results suggest that dopamine D4 receptor antagonism is not responsible for the ability of clozapine to attenuate amphetamine-induced hyperactivity and conditioned avoidance responding in rodents. Furthermore, the lack of effect of L-745,870 in these behavioral tests is consistent with the inability of the compound to alleviate psychotic symptoms in humans.
authors.affiliation: Merck, Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Harlow, Essex, CM20 2QR, United Kingdom.
authors.forename: L J
authors.initials: LJ
authors.lastname: Bristow
authors.forename: N
authors.initials: N
authors.lastname: Collinson
authors.forename: G P
authors.initials: GP
authors.lastname: Cook
authors.forename: N
authors.initials: N
authors.lastname: Curtis
authors.forename: S B
authors.initials: SB
authors.lastname: Freedman
authors.forename: J J
authors.initials: JJ
authors.lastname: Kulagowski
authors.forename: P D
authors.initials: PD
authors.lastname: Leeson
authors.forename: S
authors.initials: S
authors.lastname: Patel
authors.forename: C I
authors.initials: CI
authors.lastname: Ragan
authors.forename: M
authors.initials: M
authors.lastname: Ridgill
authors.forename: K L
authors.initials: KL
authors.lastname: Saywell
authors.forename: M D
authors.initials: MD
authors.lastname: Tricklebank
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001058:Apomorphine / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D018492:Dopamine Antagonists / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D050638:Receptors, Dopamine D4
chemical_list: C099630:3-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-1H-pyrrolo(2,3-b)pyridine; D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; C493600:Drd4 protein, mouse; C493601:Drd4 protein, rat; D011725:Pyridines; D011758:Pyrroles; D050638:Receptors, Dopamine D4; D000661:Amphetamine; D001058:Apomorphine