L-745870

L-745870 is a potent, selective, brain-penetrant and orally active dopamine D₄ receptor antagonist with a K_i of 0.43 nM. L-745870 shows weaker affinity for D₂ (K_i of 960 nM) and D₃ (K_i of 2300 nM) receptors, and exhibits moderate affinity for 5-HT₂ receptors, sigma sites and α-adrenoceptors^[1][2][3]. IC50 & Target: Ki: 0.43 nM (Human dopamine D₄ receptor), 960 nM (Human dopamine D₂ receptor), 2300 nM (Human dopamine D₃ receptor)^[1][3] In Vitro: L-745870 is capable of antagonizing the ability of D₄ receptors to inhibit agonist-induced stimulation of [³⁵S]-GTPgS binding; blocking the inhibition of forskolin-stimulated adenylate cyclase activity in transfected human embryonic kidney (HEK293) and Chinese hamster ovary (CHO) cells; blocking dopamine-induced inhibition of Ca²⁺ currents in transfected GH4C1 pituitary cells; inhibiting D₄ activation of cloned G protein-coupled inwardly rectifying K⁺ channels; and antagonizing dopamine-induced stimulation of extracellular acidification in transfected cells^[1]. In Vivo: L-745870 has good pharmacokinetic properties (20-60% oral bioavailability and plasma t_1/2 2.1-2.8 hours) in both rat and monkey, and excellent brain penetration with high brain to plasma ratios in rat^[2].
Following oral administration to squirrel monkeys, L745870 (10 mg/kg p.o.) induces mild sedation and extrapyramidal motor symptoms, notably bradykinesia, became apparent at 30 mg/kg. Lower doses of L-745870 has no observable behavioural effects in monkeys^[2].