Patel S, Freedman S, Chapman K L, Emms F, Fletcher A E, Knowles M, Marwood R, Mcallister G, Myers J, Curtis N, Kulagowski J J, Leeson P D, Ridgill M, Graham M, Matheson S, Rathbone D, Watt A P, Bristow L J, Rupniak N M, Baskin E, Lynch J J, Ragan C I
Department of Biochemistry & Molecular Biology, Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road Harlow, Essex, U.K.
J Pharmacol Exp Ther. 1997 Nov;283(2):636-47.
L-745,870,(3-([4-(4-chlorophenyl)piperazin-1-yl]methyl)-1H- pyrollo[2,3-b] pyridine, was identified as a selective dopamine D4 receptor antagonist with excellent oral bioavailability and brain penetration. L-745,870 displaced specific binding of 0.2 nM [3H] spiperone to cloned human dopamine D4 receptors with a binding affinity (Ki) of 0. 43 nM which was 5- and 20-fold higher than that of the standard antipsychotics haloperidol and clozapine, respectively. L-745,870 exhibited high selectivity for the dopamine D4 receptor (>2000 fold) compared to other dopamine receptor subtypes and had moderate affinity for 5HT2, sigma and alpha adrenergic receptors(IC50 < 300 nM). In vitro, L-745,870 (0.1-1 microM) exhibited D4 receptor antagonist activity, reversing dopamine (1 microM) mediated 1) inhibition of adenylate cyclase in hD4HEK and hD4CHO cells; 2) stimulation of [35S] GTPgammaS binding and 3) stimulation of extracellular acidification rate, but did not exhibit any significant intrinsic activity in these assays. Although standard antipsychotics increase dopamine metabolism or plasma prolactin levels in rodents, L-745,870 (</=30 mg/kg p.o.) had no effect in these assays. The lack of a suitable in vivo assay for D4 receptor activation prompted the use of in vivo surrogate marker assays which confirmed that doses of 5-60 microg/kg L-745,870 would be sufficient to occupy 50% D4 receptors in the brain. These results show that dopamine D4 receptor antagonism in the brain does not result in the same neurochemical consequences (increased dopamine metabolism or hyperprolactinemia) observed with typical neuroleptics.
L-745,870（3-([4-(4-氯苯基)哌嗪-1-基]甲基)-1H-吡咯并[2,3-b]吡啶）被鉴定为一种选择性多巴胺D4受体拮抗剂，具有出色的口服生物利用度和脑渗透性。L-745,870以0.43 nM的结合亲和力（Ki）取代了0.2 nM [3H]螺哌隆与克隆的人多巴胺D4受体的特异性结合，分别比标准抗精神病药物氟哌啶醇和氯氮平高5倍和20倍。与其他多巴胺受体亚型相比，L-745,870对多巴胺D4受体表现出高选择性（>2000倍），对5HT2、σ和α肾上腺素能受体具有中等亲和力（IC50 < 300 nM）。在体外，L-745,870（0.1-1 microM）表现出D4受体拮抗剂活性，逆转多巴胺（1 microM）介导的：1）hD4HEK和hD4CHO细胞中腺苷酸环化酶的抑制；2）[35S]GTPγS结合的刺激；3）细胞外酸化速率的刺激，但在这些试验中未表现出任何显著的内在活性。尽管标准抗精神病药物会增加啮齿动物的多巴胺代谢或血浆催乳素水平，但L-745,870（口服剂量≤30 mg/kg）在这些试验中没有效果。缺乏合适的D4受体激活体内试验促使使用体内替代标志物试验，该试验证实5-60 microg/kg的L-745,870剂量足以占据脑中50%的D4受体。这些结果表明，脑中多巴胺D4受体拮抗作用不会导致与典型抗精神病药物相同的神经化学后果（多巴胺代谢增加或高催乳素血症）。
