Summary overview of microdialysis, behavioral, and gene expression effects of IRL752 and selected procognitive comparators

Sources for comparator data cited: Atomoxetine: Bymaster et al., 2002; Swanson et al., 2006; Tzavara et al., 2006; Cain et al., 2011; IRL AB, unpublished data. Methylphenidate: Gerasimov et al., 2000; Bymaster et al., 2002; Marsteller et al., 2002; Berridge et al., 2006; Tzavara et al., 2006; Banerjee et al., 2009; Seu and Jentsch, 2009; Rowley et al., 2014; IRL AB, unpublished data. Clozapine: Hertel et al., 1997; Westerink et al., 2001; Ichikawa et al., 2002; Shirazi-Southall et al., 2002; Devoto et al., 2003; Shilliam and Dawson, 2005; Abdul-Monim et al., 2006; Grayson et al., 2007; Robbins et al., 2008; IRL AB, unpublished data. Cariprazine: Neill et al., 2016; Kehr et al., 2018; Huang et al., 2019; Waters et al., 2020; IRL AB, unpublished data. Vortioxetine: Mørk et al., 2013; Pehrson et al., 2013, 2018; du Jardin et al., 2014; Wallace et al., 2014; IRL AB, unpublished data. Atipamezole: Kauppila et al., 1991; Haapalinna et al., 1998; Tellez et al., 1999; Devoto et al., 2003; Lapiz and Morilak, 2006; Bondi et al., 2010; Mervaala et al., 1993; IRL AB, unpublished data. Idazoxan: Devauges and Sara, 1990; Coull et al., 1996; Hertel et al., 1997; Tellez et al., 1999; Swanson et al., 2006; Uys et al., 2017b; IRL AB, unpublished data. Fluparoxan: Tellez et al., 1999; Millan et al., 2000; Borthwick, 2017; IRL AB, unpublished data. Disclaimer: Permutations of experimental conditions and differences in set-ups between laboratories preclude direct head-to-head comparisons of efficacies and responses among agents. This applies broadly but may be particularly apparent with regard to cognitive behavioral testing.

Key targetsNATDAT, NAT5-HT2, α2, H1D3, D2, 5-HT1ASERT, 5-HT3α2α2α25-HT7, α2, SERT, σ1
ProcognitiveYes (ADHD)Yes (ADHD)Yes (Schiz)Yes (Schiz)Yes (Depr)VariableVariableVariableTBD
Dose range0.3–3 mg/kg = 1.2–12 µmol/kg, i.p.0.5–30 mg/kg = 2.15–129 µmol/kg, i.p. or p.o.0.1–100 mg/kg = 0.3–300 µmol/kg, s.c., i.p., or p.o.0.2–3 mg/kg = 0.23–7 µmol/kg, p.o. or s.c.2.5–10 mg/kg = 8.4–34 µmol/kg, s.c.0.5–4.5 mg/kg = 2.4–21.2 µmol/kg, i.p. or s.c.0.25–20 mg/kg = 1.23–98 µmol/kg, i.p. or s.c.0.63–10 mg/kg = 3.2–51.3 µmol/kg, s.c. or i.p.10.6 mg/kg = 50 µmol/kg, s.c.
NA PFCIncrease (∼300)Increase (∼290)Increase (∼350–390)No effectIncrease (∼270)Increase (∼250)Increase (∼250)Increase (∼240)Increase (∼380)
DA PFCIncrease (∼325)Increase (∼350)Increase (∼360–400)No effectIncrease (∼275)Increase (∼260)Increase (∼210)Increase (∼150)Increase (∼285)
DOPAC PFCIncrease (∼150)No effectIncrease (∼250)N/AIncrease (∼150)Increase (∼180)Increase (∼135)Increase (∼180%)No effect
5-HT PFCNo effectNo effectDecrease (∼45)No effectIncrease (∼410)Increase (∼160)No effectNo effectIncrease (∼220)
DA StriNo effectIncrease (∼210–250)Increase (∼150–170)N/ANo effectNo effectNo effectNo effectNo effect
DOPAC StriNo effectN/AIncrease (∼190)N/ANo effectNo effectNo effectNo effectNo effect
5-HT StriIncrease (∼150)Increase (∼320)Decrease (∼65)N/AIncrease (∼360)No effectDecrease (∼50)Decrease (∼70)Increase (∼170)
ACh PFCIncrease (∼300)Increase (∼250–300)Increase (∼500–625)No effectIncrease (∼230)Increase (∼250)Increase (∼275)Increase (∼300)Increase (∼250)
LMA normalNo effectIncreaseDecreaseDecreaseNo effectNo effectNo effectIncreaseNo effect
IEGs FcxNo effectIncrease (Arc)No effectNo effectNo effectIncrease (Arc)No effectIncrease (Arc, c-fos)Increase (Arc, c-fos)
IEGs StriNo effectIncrease (Arc)Increase (c-fos)Increase (Arc, c-fos)Increase (Arc)Increase (Arc, c-fos)Increase (Arc, c-fos)Increase (Arc, c-fos)Increase (Arc, c-fos)
RL or ASSTYesYesYesYesYesYesYesN/AYes
  • Figures in brackets refer to approximate peak level (% of corresponding baseline). DAT, dopamine transporter; ADHD, Attention Deficit Hyperactive Disorder; ASST, Attentional Set-Shifting Test; Depr, Depressive disorder; LMA, locomotor activity; N/A, data not available; No effect, not significantly different from corresponding control treatment; Schiz, Schizophrenia; Stri, striatum; Fcx, frontal cortex; TBD, To be determined.