TABLE 4.
Most common Sigmar1 ligands cited in this manuscript with their respective affinities and selectivity.
| Ligand | Binding Affinity | Effect on Sigmar1 | Effect on Sigmar2 | Selectivity for others | Pleiotropic effects |
| PRE-084 | Sigmar1 (Ki 44–53 nM) > Sigmar2 (Ki 32.1 μM) (Su et al., 1991; Garcés-Ramírez et al., 2011) | Agonist (Maurice et al., 1994b; Hayashi and Su, 2007; Garcés-Ramírez et al., 2011; Hyrskyluoto et al., 2013; Gao et al., 2018) | − | Low binding affinity for dopamine D2, muscarinic acetylcholine, serotonin, and adrenergic receptors (Su et al., 1991) | − |
| SA4503 (cutamesine) | Sigmar1 (Ki 4.6 nM) > Sigmar2 (Ki 63.1 nM) (Matsuno et al., 1996) | Agonist (Kobayashi et al., 1996; Matsuno et al., 1996) | − | Little affinity for 36 other receptors, ion channels and second messenger systems (Matsuno et al., 1996) | − |
| (+) Pentazocine | Sigmar1 (Ki 3.9–23.3 nM) > Sigmar2 (Ki 1,542–6,611 nM) (Hellewell et al., 1994; John et al., 1999) | Agonist (Pan et al., 2014; Mishra et al., 2015) | Binds at low affinity (Hellewell and Bowen, 1990) | k-opioid receptor-partial agonist (analgesic), enhances acetylcholine release (Hiramatsu and Hoshino, 2005), low affinity partial agonist to mu receptor (Chien and Pasternak, 1994) | − |
| ANAVEX 2-73 (blarcamesine) | Moderate Sigmar1 (Ki 860 nM) (Villard et al., 2011) | Agonist (Vamvakidès, 2002; Villard et al., 2011; Christ et al., 2019) | − | Muscarinic acetylcholine receptor-inhibitor (Villard et al., 2011; Christ et al., 2019) | − |
| (+)-SKF-10047 | Sigmar1 (Ki 54–597 nM) > Sigmar2 (Ki 11.17–39.74 μM) (Hellewell et al., 1994; Vilner and Bowen, 2000) | Agonist (Hellewell et al., 1994; Vilner and Bowen, 2000) | − | NMDA receptor antagonist, enhances acetylcholine release (Hiramatsu and Hoshino, 2005) | Inhibits Nav channels in Sigmar1 knockout cells (Johannessen et al., 2009, 2011) |
| Fluvoxamine | Sigmar1 (Ki 36 nM) > Sigmar2 (Ki 8,439 nM) (Narita et al., 1996) | Agonist (Narita et al., 1996; Tagashira et al., 2010; Bhuiyan et al., 2011b) | − | Serotonin reuptake inhibitor (Fu et al., 2012; Narita et al., 1996) | − |
| DTG | Sigmar1 (Ki 38–203 nM) =Sigmar2 (Ki13–58 nM) (Koe et al., 1989; Hellewell et al., 1994; Vilner and Bowen, 2000) | Agonist (Walker et al., 1992; Marrazzo et al., 2011; Zampieri et al., 2016) | Agonist (Walker et al., 1992; Marrazzo et al., 2011; Zampieri et al., 2016) | − | Inhibits Nav channels in Sigmar1 knockout cells (Johannessen et al., 2009, 2011) |
| DHEA | Moderate Sigmar1 (Ki 2.96 μM) (Maurice et al., 1996) | Agonist (Monnet et al., 1995; Waterhouse et al., 2007) | − | Neurosteroid, NMDA receptors, GABA-A receptors, nuclear receptor (Wu et al., 1991; Paul and Purdy, 1992; Waterhouse et al., 2007) | − |
| Cocaine | Sigmar1 (Ki 2.5–19 μM) > Sigmar2 (Ki 31 μM) (McCann and Su, 1991; Matsumoto et al., 2002; Garcés-Ramírez et al., 2011) | Agonist (Hayashi and Su, 2001, 2007; Matsumoto et al., 2002) | − | Dopamine transporters, Neurotransmitter reuptake blocker (Matsumoto et al., 2002; Beggiato et al., 2017) | − |
| 4-IBP | Sigmar1 (Ki 1.70 nM) > Sigmar2 (Ki 25.2 nM) (John et al., 1995, 1998) | Agonist (Amer et al., 2013) Inverse agonist (Bermack and Debonnel, 2005; Schmidt et al., 2016) | Antagonist (John et al., 1995, 1998) | − | Inhibits Ca2+ entry and block TRPCs and TRPMs in the absence of Sigmar1 (Amer et al., 2013) |
| PPBP | Sigmar1 (Ki 0.8 nM) = Sigmar2 (Ki 1.14 nM) (Glennon et al., 1991; Hashimoto and London, 1993) | Agonist (Goyagi et al., 2001; Nishimura et al., 2008; Yang et al., 2010) | − | nNOS inhibitor (Goyagi et al., 2001; Yang et al., 2010) | − |
| Fabomotizole (Afobazole) | Moderate Sigmar1 (Ki 5.9 μM) (Seredenin and Voronin, 2009) | Agonist (Katnik et al., 2016) | Agonist (Katnik et al., 2016) | Melatonin receptors (MT1 and MT3), MAO-A receptive site (Kryzhanovskii et al., 2018) | − |
| Pridopidine | Sigmar1 (Ki 57 nM) > Sigmar2 (Ki 5,450 nM) (Johnston et al., 2019) | Agonist (Shenkman et al., 2021; Dyhring et al., 2010; Johnston et al., 2019) | Binds at comparatively lower affinity (Johnston et al., 2019) | adrenergic-α2C, Dopamine D2 and D3 receptors, serotoninergic-5HT1A (Dyhring et al., 2010; Johnston et al., 2019) | − |
| Haloperidol | Sigmar1 (Ki 1–40 nM) Sigmar2 (Ki 12–221 nM) (Su et al., 1988: Hellewell et al., 1994; Vilner and Bowen, 2000; Choi et al., 2001) | Antagonist (Hellewell and Bowen, 1990; Hellewell et al., 1994; Mishra et al., 2015) | Antagonist (Hellewell and Bowen, 1990; Hellewell et al., 1994; Choi et al., 2001) | Dopamine (D2 and D3) receptor antagonist (Fox et al., 1994) | − |
| Sertraline | Sigmar1 (Ki 57 nM) > Sigmar2 (Ki 5,297 nM) (Narita et al., 1996) | Antagonist (Ishima et al., 2014) Inverse Agonist (Matsushima et al., 2019) | − | Serotonin reuptake inhibitor (Ishima et al., 2014) | − |
| PB28 | Sigmar2 (Ki 0.28 nM) > Sigmar1 (Ki 10 nM) (Azzariti et al., 2006) | Antagonist (low affinity) (Azzariti et al., 2006) | Agonist (Azzariti et al., 2006) | − | Inhibits Nav channels, and Kv2.1 current in the absence of Sigmar1 (Johannessen et al., 2009, 2011; Liu et al., 2017) |
| NE-100 | Sigmar1 (Ki 1.5 nM) > Sigmar2 (Ki 84.6 nM) (Okuyama et al., 1993) | Antagonist (Tanaka et al., 1995; Ono et al., 2013) | In vivo regulation of serotonin 5-HT2a receptors (Hashimoto et al., 1997) | Inhibits Kv2.1 current in the absence of Sigmar1 (Liu et al., 2017) | |
| E-5842 | Sigmar1 (Ki 4 nM) > Sigmar2 (Ki 220 nM) (Guitart and Farré, 1998; Guitart et al., 1998; Romero et al., 2000) | Antagonist (Zamanillo et al., 2000) | − | Dopamine receptors, serotonin receptors, acetylcholine and muscarinic receptors, adrenergic receptors (Guitart and Farré, 1998) | Induces micronucleated polychromatic erythrocyte-dependent hypothermia in Sigmar1 null mice (Guzmán et al., 2008) |
| BD1047 | Sigmar1 (Ki 0.6–5.3 nM) > Sigmar2 (Ki 47 nM) (Matsumoto et al., 1995) | Antagonist (Matsumoto et al., 1995; Pan et al., 2014) | Binds with 10 times lower affinity (Matsumoto et al., 1995) | Beta adrenergic receptor ligand (Matsumoto et al., 1995) | Inhibits Ca2+ entry and block TRP channels, and Kv2.1 current in the absence of Sigmar1 (Amer et al., 2013; Liu et al., 2017) |
| BD1063 | Sigmar1 (Ki 47 nM) > Sigmar2 (Ki 449 nM) (Matsumoto et al., 1995) | Antagonist (Matsumoto et al., 1995; Pan et al., 2014) | − | − | Inhibits Ca2+ entry and block TRP channels in the absence of Sigmar1 (Amer et al., 2013) |
| SM21 | − | − | Antagonist (Ghelardini et al., 2000) | − | Inhibits Kv2.1 current in the absence of Sigmar1 (Liu et al., 2017) |
| Methamphetamine | − | Antagonist (Hayashi and Su, 2007) Inverse agonist (Yasui and Su, 2016) | − | Dopamine Transporters, Monoamine transporters (Siciliano et al., 2014; McFadden et al., 2015) | − |
| IPAG | Sigmar1 (Ki 3 nM) > Sigmar2 (Ki 500–8000 nM) (Brimson et al., 2011; Schrock et al., 2013) | Antagonist (Schrock et al., 2013; Maher et al., 2018) | − | − | − |