Table 1.

Experimental Serotonergic Agents in Schizophrenia

Serotonergic Agent	Properties	Other Binding Sites	References
Bifeprunox (DU-127090)	- Partial agonist at presynaptic 5-HT1ARs (pKi=8.2) - Partial agonist at presynaptic D2Rs (pKi=8.5)	− 5HT2A, 5HT2CRs (pKi<6) - M and H1Rs (pKi<6)	- Bruins et al, 2005 [21] - Tadori et al, 2007 [22] - Stahl, 2002 [23]
8-OH-DPAT	- Agonist at presynaptic 5-HT1ARs (pKi=9.0)	−5-HT1B (pKi=6.2), 5-HT1D (pKi=6.8), 5-HT7Rs (pKi=6.4) - D2, α1,α2Rs (pKi≤6)	- Assié and Koek, 2000 [29]
LASSBio-579	- Agonist at presynaptic 5-HT1ARs (Ki=0.22 μM) - Antagonist at postsynaptic D2-like (Ki=0.39 μM) and D4Rs (Ki=0.18 μM)	− 5-HT2A, 5-HT2CRs (Ki around 7 μM) - MRs (Ki>30 μM), α1B and α2Rs (Ki=2.6 μM)	- Pompeu et al, 2013 [33] - Neves et al, 2013 [34]
SB-773812	-Antagonist at postsynaptic 5-HT2ARs (pKi=8.5) - Antagonist at D3Rs (pKi=9.0)*	- D2Rs (pKi=7)	- Catafau et al, 2011 [35]
AM-831	- Antagonist at postsynaptic 5-HT2ARs** - Antagonist at postsynaptic D2Rs(antagonist)**	- M1Rs**	ACADIA Pharmaceuticals Advances, 2011 [37]
Zicronapine (Lu 31–130)	- Antagonist at postsynaptic 5-HT2ARs (Ki=4.2 nM) -Antagonist at postsynaptic D1 and D2Rs (Ki=19 nM)	N/A	- Citrome, 2013 [39]
Vabicaserin (SCA-136)	-Agonist at postsynaptic 5-HT2CRs (Ki=3 nM)	− 5HT1A (Ki=112 nM), 5-HT2BRs (Ki=14nM) - More than 50-fold selective on Receptors such as other 5-HT, D and α1Rs (Ki≥152nM)	- Liu et al, 2014 [41]
AS2030680	- Antagonist at presynaptic 5-HT5ARs (Ki=0.58 ± 0.17 nM)	−5-HT1A (Ki=20.7 nM), 5-HT2B (Ki= 22.0 nM), 5-HT6 (Ki=39.3 nM), 5HT7Rs (Ki=10.3 nM), other 5-HTRs (Ki>300 nM)	Yamazaki et al, 2015 [43]
AS2674723	- Antagonist at presynaptic 5-HT5ARs (Ki=0.75 ± 0.03 nM)	− 5-HT1A (Ki=83.8 nM), 5-HT7Rs (Ki=7.3 nM); other 5-HTRs (Ki>300 nM)	Yamazaki et al, 2015 [43]
ASP5736	-Antagonist at presynaptic 5-HT5ARs (Ki=3.6 ± 0.66 nM)	− 5-HT2CR (Ki=286.8 nM); other 5-HTRs (Ki > 1000 nM)	Yamazaki et al, 2015 [43,44]
SB699551	- Antagonist at presynaptic 5-HT5ARs (pKi=8.5)	− 5-HT1A and 5-HT7Rs (pKi<5.5); 5-HT1B,5-HT1D, 5-HT2A and 5-HT2C (pKi<6)	Thomas et al, 2006 [46]
AVN-211	Antagonist at postsynaptic 5-HT6Rs (Ki=2.1 nM)	− 5-HT2BRs (Ki=125nM); within the other 5-HTRs group the compound showed about 100-fold less than 5-HT6R selectivity.	-Ivachtchenko et al, 2016 [47]
Idalopirdine (Lu-AE58054)	- Antagonist at postsynaptic 5-HT6Rs (Ki=0.83±0.12 nM)	−5-HT2A (Ki=83±17nM), 5-HT2CRs (Ki=250±23nM); other 5-HTRs: over 400-fold less affinity than for 5-HT6Rs - α1ARs (Ki=21 nM), α1BRs (Ki=22nM)	- Arnt et al, 2010 [50]
RU-24969	- Agonist at pre-synaptic 5-HT1A (pKi=9) and 5-HT1BRs (pKi=8.1)	− 5-HT1D (pKi=7.7), 5HT2B (pKi=6.9), 5HT2A (pKi=6.9), 5HT2C (pKi=6.8),5HT5A (pKi=6), 5HT6 (pKi=6.2), 5HT7Rs (pKi=6.9)	- Cassaday et al, 1993 [30]
Ritanserin	Antagonist at postsynaptic 5-HT2AR (pKi=9.2) and 5-HT2CRs (pKi=8.2–9.6)	− 5-HT2BRs (pKi=8.3); other 5-HTRs (pKi≦7.8) - D2 (pKi=5.8), H1 (pKi<5), α1 (pKi=6.6–7.1) and α2Rs (pKi=6.5–7)	- Leysen et al, 1985 [53]
LuAF-35700	- Antagonist at postsynaptic 5-HT2A and 5-HT6Rs** - Antagonist at postsynaptic D1>D2Rs**	N/A	https://clinicaltrials.gov/ct2/show/NCT03230864 [54]
Brilaroxazine (RP5063)	- Partial agonism at presynaptic 5-HT1A (Ki=1.5nM) and postsynaptic 5-HT2A (Ki=2.5 nM); - Antagonism at presynaptic 5-HT2B (Ki=0.19 nM), postsynaptic 5-HT6**, and 5-HT7Rs (Ki=2.7 nM) - Partial agonism at D2, D3 and D4Rs**	-SERT and nAChRα4β2**	- Cantillon et al, 2017 [56]

Notes: *Unspecified pre or post-synaptic targets; **Unspecified degree of affinity binding.

Abbreviations: 5-HTR, 5-hydroxytryptamine receptor; 8-OH-DPAT, 8-hydroxy-2-(di-n-propylamino) tetralin; αR, adrenoreceptor; DR, dopamine receptor; H, histamine; Ki, the inhibitory constant; LASSBio-579, [1-((1-(4-chlorophenyl)-1H-pyrazol-4-yl)methyl)-4-phenylpiperazine]; MR, muscarinic receptor; μM, micromole; nAChRs, Nicotinic acetylcholine receptors; nM, nanomole; pKi, the negative log (base 10) of the Ki value eg pKi, -log10(Ki); SERT, serotonin transporter; N/A, not available.