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data cited: Atomoxetine: Bymaster et al., 2002; Swanson et al., 2006; Tzavara et al., 2006; Cain et al., 2011; IRL AB, unpublished data.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Berridge et al., 2006; Tzavara et al., 2006; Banerjee et al., 2009; Seu and Jentsch, 2009; Rowley et al., 2014; IRL AB, unpublished data.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et al., 2003; Shilliam and Dawson, 2005; Abdul-Monim et al., 2006; Grayson et al., 2007; Robbins et al., 2008; IRL AB, unpublished data. Cariprazine: Neill et al., 2016; Kehr et al., 2018; Huang et al., 2019; Waters et al., 2020; IRL AB, unpublished data. Vortioxetine: Mørk et al., 2013; Pehrson et al., 2013, 2018; du Jardin et al., 2014; Wallace et al., 2014; IRL AB, unpublished data.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Tellez et al., 1999; Devoto et al., 2003; Lapiz and Morilak, 2006; Bondi et al., 2010; Mervaala et al., 1993; IRL AB, unpublished data.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1990; Coull et al., 1996: Hertel et al., 1997; Tellez et al., 1999; Swanson et al., 2006; Uys et al., 2017b; IRL AB, unpublished data. Fluparoxan: Tellez et al., 1999;Millan et al., 2000; Borthwick, 2017; IRL AB, unpublished data.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
Procognitive Dose rangeYes (ADHD) 0.3-3 mg/kg = 1.2-12 μmol/kg, i.p.Yes(ADHD) 0.5-30 mg/kg = 2.15-129 μmol/kg, i.p. or p.o.Yes (Schiz) 0.1-100 mg/kg = 0.3-300 μmol/kg, s.c., i.p., or p.o.Yes (Schiz) 0.2-3 mg/kg = 0.23-7 μmol/kg, p.o. or s.c.Yes (Depr) 2.5-10 mg/kg = 8.4-34 μmol/kg, s.c.Variable 0.5-4.5 mg/kg = 2.4-21.2 μmol/kg, i.p. or s.cVariable 0.25-20 mg/kg = 1.23-98 μmol/kg, i.p. or s.cVariable 0.63-10 mg/kgv= 3.2-51.3 μmol/kg, s.c. or i.p.TBD 10.6 mg/k g= 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 PFC 5-HT PFCIncrease(∼150)No effectIncrease(∼250)N/AIncrease(∼150)Increase(∼180)Increase(∼135)Increase(∼180%)No effect
No effectNo effectDecrease(∼25)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 FEXNo 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.