TABLE 1

Summary of the effects of A-867744

Receptor Assay System EC50 or Ki (mean, 95% confidence interval) Max (Mean ± S.E.M.) n
μM %
α7 nAChR functional studies
   Human α7 ACh-evoked current in X. laevis oocytes 1.12 (0.55–2.31) 733 ± 146a 4–7
   Rat α7b ACh-evoked current in X. laevis oocytes 0.98 (0.53–1.80) 418 ± 47a 6
   Human native α7*b Agonist-evoked Ca2+ transient in IMR-32 neuroblastoma cells 1.92 (1.12–3.28) 100c 5
   Rat native α7* Choline-evoked current in CA1 hippocampus interneurons 193a and 340a increases in peak current and total charge (see Table 2) 4
Functional selectivity
   Human α3β4 Nicotine-evoked Ca2+ transient in HEK-293 cells IC50 = 19.5 (14.2–26.8) Inhibition: 64 ± 4 3–5
   Human α4β2 Nicotine evoked Ca2+ transient in HEK-293 cells IC50 = 6.4 (4.8–8.6) Inhibition: 96 ± 1 6–8
   Human 5-HT3A 5-HT-evoked current in X. laevis oocytes >30 93 ± 18a 2–4
   Human α7/5-HT3 chimera PNU-282987 evoked FMP increase in HEK-293 cells >10 85 ± 7a 6
   Human α7/5-HT3 chimera ACh-evoked current in HEK-293 cells 55 ± 7 inhibition at 10 μM 5
Radioligand binding studies
   Rat native α7* Displacement of [3H]MLA binding in rat brain >10 Inactived 3
   Rat native α7* Displacement of [3H]A-585539 binding in rat brain 0.023 (0.012–0.041) 79 ± 5d 7
   Human α7/5-HT3 chimera Displacement of [3H]A-585539 binding in HEK-293 cells >10 Inactived 3
  • a Effect normalized to submaximal agonist effect of ACh, nicotine, PNU-282987, or 5-HT (i.e., 100% means no effect using this normalization)

  • b Data from Faghih et al. (2009)

  • c Effect normalized to maximal effect of A-867744

  • d Percentage of specific displacement