L-741,626

L-741,626 is an antagonist of the dopamine D₂ receptor (K_is = 2.4, 100, and 220 nM for human D₂, D₃, and D₄, respectively, in a radioligand displacement assay).¹ L-741,626 is selective for D₂ receptors (K_i = 3.98 nM) over serotonin receptors (K_is ≤ 316.2 nM for human 5-HT_1A, 5-HT_1B, 5-HT_1D, 5-HT_2A, 5-HT_2B, 5-HT_2C, and 5-HT₃).² In a functional assay, L-741,626 inhibits quinpirole-stimulated mitogenesis with EC₅₀ values of 4.46 and 90.4 nM in CHO cells transfected with human D_2long and D₃ receptors, respectively.³ L-741,626 (3 μM) reversibly blocks D₂-mediated currents in Xenopus oocytes via G protein-gated inwardly rectifying K⁺ (GIRK) channels.⁴ In models of potential antipsychotic activity, L-741,626 inhibits apomorphine-induced climbing behavior in mice (ID₅₀ = 0.3 mg/kg, s.c.) and the conditioned avoidance response (CAR) in rats (ID₅₀ = 6.1 mg/kg, s.c.).⁵ L-741,626 evokes a catalepsy response (AD₅₀ = 7.0 mg/kg, s.c.) and blocks gnawing induced by methylphenidate (Item No. 11639; ID₅₀ = 2.4 mg/kg, s.c.) in rat models of potential extrapyramidal activity.

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1. Kulagowski, J.J., Broughton, H.B., Curtis, N.R., et al. 3-((4-(4-Chlorophenyl)piperazin-1-yl)-methyl)-1H-pyrrolo[2,3-b]pyridine: An antagonist with high affinity and selectivity for the human dopamine D₄ receptor. J. Med. Chem. 39(10), 1941-1942 (1996).

2. Millan, M.J., Gobert, A., Newman-Tancredi, A., et al. S33084, a novel, potent, selective, and competitive antagonist at dopamine D₃-receptors: I. Receptorial, electrophysiological and neurochemical profile compared with GR218,231 and L741,626. J. Pharmacol. Exp. Ther. 293(3), 1048-1062 (2000).

3. Grundt, P., Husband, S.L., Luedtke, R.R., et al. Analogues of the dopamine D₂ receptor antagonist L741,626: Binding, function, and SAR. Bioorg. Med. Chem. Lett. 17(3), 745-749 (2007).

4. Pillai, G., Brown, N.A., McAllister, G., et al. Human D₂ and D₄ dopamine receptors couple through βγ G-protein subunits to inwardly rectifying K⁺ channels (GIRK1) in a Xenopus oocyte expression system: selective antagonism by L-741,626 and L-745,870 respectively. Neuropharmacology 37(8), 983-987 (1998).

5. Millan, M.J., Dekeyne, A., Rivet, J.M., et al. S33084, a novel, potent, selective, and competitive antagonist at dopamine D₃-receptors: II. Functional and behavioral profile compared with GR218,231 and L741,626. J. Pharmacol. Exp. Ther. 293(3), 1063-1073 (2000).