title: KKHA-761, a potent D3 receptor antagonist with high 5-HT1A receptor affinity, exhibits antipsychotic properties in animal models of schizophrenia.
abstract: KKHA-761, 1-{4-[3-(3,4-dimethoxy-phenyl)-isoxazol-5-yl]-butyl}-4-(2-methoxy-phenyl)-piperazine, has a high affinity (Ki=3.85 nM) for human dopamine D3 receptor with about 70-fold selectivity over the human dopamine D(2L) receptor (Ki=270 nM). KKHA-761 also showed high affinity for cloned human 5-HT1A receptor (Ki=6.4 nM). KKHA-761 exhibited D3 and 5-HT1A receptor antagonist activities in vitro, reversing dopamine- or 5-HT-mediated stimulation of [35S]GTPrS binding. The in vivo pharmacological profile of KKHA-761 was compared with both typical and atypical antipsychotics including clozapine and haloperidol. Apomorphine-induced dopaminergic behavior, cage climbing, in mice was potently blocked by a single administration (i.p.) of KKHA-761 (ID50=4.06 mg/kg) or clozapine (ID50=4.0 mg/kg). Cocaine- or MK-801-induced hyperactivity in animals was markedly inhibited by KKHA-761 or clozapine. In addition, KKHA-761 significantly reversed the disruption of prepulse inhibition (PPI) produced by apomorphine in mice, indicating the antidopaminergic or antipsychotic activity of KKHA-761 in mice. However, KKHA-761 was inactive in the forced swimming behavioral despair model in mice, suggesting lack of antidepressant properties. KKHA-761 attenuated the hypothermia induced by a selective dopamine D3 agonist, 7-OH-DPAT, in mice, whereas clozapine enhanced it. Moderate doses of both KKHA-761 and clozapine did not increase serum prolactin levels in rats. Lower doses of, however, haloperidol significantly increased prolactin secretion. KKHA-761 did not induce cataleptic response up to 20 mg/kg, but significant catalepsy was shown at lower doses of clozapine and haloperidol. Furthermore, KKHA-761 showed a low incidence of rotarod ataxia (TD50=34.4 mg/kg, i.p.) in mice. The present results, therefore, suggest that KKHA-761 is a potent antipsychotic agent with combined dopamine D3 and serotonin 5-HT1A receptors modulation activity, which may further enhance its therapeutic potential for anxiety, psychotic depression, and other related disorders.
authors.affiliation: Pharmaceutical Screening Research Team, Korea Research Institute of Chemical Technology, 100 Jang-Dong, Yuseong-Gu, Daejon 305-343, Korea. wkpark@krict.re.kr
authors.forename: Woo-Kyu
authors.initials: WK
authors.lastname: Park
authors.forename: Daeyoung
authors.initials: D
authors.lastname: Jeong
authors.forename: Heeyeong
authors.initials: H
authors.lastname: Cho
authors.forename: Seong Jin
authors.initials: SJ
authors.lastname: Lee
authors.forename: Mi Young
authors.initials: MY
authors.lastname: Cha
authors.forename: Ae Nim
authors.initials: AN
authors.lastname: Pae
authors.forename: Kyung Il
authors.initials: KI
authors.lastname: Choi
authors.forename: Hun Yeong
authors.initials: HY
authors.lastname: Koh
authors.forename: Jae Yang
authors.initials: JY
authors.lastname: Kong
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents; D001831:Body Temperature / Q000187:drug effects; D002375:Catalepsy / Q000139:chemically induced / Q000523:psychology; D002460:Cell Line; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism; D007555:Isoxazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010879:Piperazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D004856:Postural Balance / Q000187:drug effects; D011388:Prolactin / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors*; D050638:Receptors, Dopamine D4 / Q000187:drug effects / Q000378:metabolism; D013216:Reflex, Startle / Q000187:drug effects; D012559:Schizophrenia / Q000188:drug therapy*; D012565:Schizophrenic Psychology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013134:Spiperone / Q000378:metabolism; D013550:Swimming / Q000523:psychology
chemical_list: D014150:Antipsychotic Agents; D018765:Dopamine Uptake Inhibitors; D007473:Ion Channels; D007555:Isoxazoles; C508236:KKHA-761; D010879:Piperazines; D017447:Receptors, Dopamine D1; D050637:Receptors, Dopamine D3; D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D050638:Receptors, Dopamine D4; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D013134:Spiperone; D011388:Prolactin