Table 2.

Novel anxiolytic targets

Brain Target	Drug Action	Sample Compound	Behavioural Effects in animal models	Comments	References
GABA
GABAA receptors	α2 subunit specific agonists	MRK-409	Anxiolytic effects in rat elevated plus maze, conditioned startle response and punished drinking paradigms, as well as conditioned emotional response paradigm in primates	The safety and tolerability of MRK-409 were examined in humans and it was discovered to possess sedative properties, not observed in preclinical studies. Development was abandoned.	(Atack et al., 2011)
GABAB receptors	Positive allosteric modulators	GS39783	Anxiolytic effects in the light–dark box, elevated plus maze, elevated zero maze and stress-induced hyperthermia paradigm		(Cryan et al., 2004; Cryan and Kaupmann, 2005)
Glutamate
NMDA receptor	Partial agonists	d-cycloserine	Facilitates fear extinction in rodents	Effective in reducing conditioned fear responses in acrophobic patients	(Ressler et al., 2004; Amaral and Roesler, 2008)
mGluR2/3	Agonists	LY354740, LY314582, APDC	Block expression of fear potentiated startle in rats, anxiolytic effects in the EPM in mice and rats, anxiolytic effects in mouse and rat conflict tests, attenuates lactate-induced panic in rats, anxiolytic in the SIH paradigm reduces startle response following drug of abuse withdrawal in rats.	LY544344, a prodrug of LY354740 with improved oral bioavailabilty, has shown efficacy and tolerability in human GAD patients. Discontinued.	(Monn et al., 1997; Helton et al., 1998; Benvenga et al., 1999; Kłodzińska et al., 1999; Spooren et al., 2002; Dunayevich et al., 2008)
mGluR2	Positive allosteric modulators	4-MPTTS, CBiPES, ADX71149	Block expression of fear-potentiated startle in rats and has an anxiolytic effect in the rat SIH paradigm	ADX71149 is in phase 2 clinical trials	(Johnson et al., 2005, Addex company website)
mGluR4	Agonists	LSP1-2111	Anxiolytic effects in the EPM and reduces the SIH response in mice. Reduction in the SIH response in diminished in 5HT-depleted animals.		(Wierońska et al., 2010)
mGluR5	Antagonists	MPEP, MTEP	MPEP has anxiolytic effects in the Geller–Seifter test, the Vogel punished drinking test, conditioned emotional response paradigm, as well as in the social interaction test, defensive marble burying, the elevated plus maze and the SIH paradigm		(Kuhn et al., 2002; Spooren and Gasparini, 2004; Ballard et al., 2005; Varty et al., 2005)
mGluR7	Agonists	AMN082	Anxiolytic effects in the four-plate test and reduces the SIH response in mice. Facilitates extinction of amygdala-dependent fear conditioning and inhibits acquisition of Pavlovian fear conditioning.		(Fendt et al., 2008; Stachowicz et al., 2008)
mGluR8	Agonist/positive allosteric modulator	DCPG (agonist) AZ12216052 (Positive allosteric modulator)	Anxiolytic effects in the elevated zero maze and acoustic startle paradigm (positive modulator only)		(Duvoisin et al., 2010)
Serotonin
5-HT7 receptor	Antagonist	SB269970	Anxiolytic in the elevated plus maze, Vogel punished drinking and four-plate test		(Wesolowska et al., 2006)
5-HT1A receptor	Antagonists	WAY100635, p-MPP, ISL88.0338	Anxiolytic in the mouse defensive test battery		(Griebel et al., 1999)
5-HT2C receptor	Antagonists	S32006	Anxiolytic in the defensive marble-burying paradigm, Vogel punished drinking and social interaction tests		(Dekeyne et al., 2008; Wacker and Miller, 2008)
Neuropeptide systems
CRH1 receptor	Antagonists	Antalarmin, pexacerfont, GSK561679, CP154-526	Anxiolytic effects across a wide range of behavioural tests and between a variety of species.	Pexacerfont failed in to improve anxiety symptoms in generalized anxiety disorder in a randomized control trial. GSK561679 is currently undergoing clinical trials for anxiety disorders.	(Kehne & De Lombaert, 2002; Takahashi, 2001; Coric et al., 2010)
CRH2 receptor	Antagonists	Anti-savagine-30	Anxiolytic effects in the elevated plus maze, conditioned freezing and defensive behaviour.		(Takahashi, 2001)
NK1 receptor	Antagonists	Vestipitant	Anxiolytic effects on fear-induced foot tapping and social interaction in gerbils, USVs in guinea pigs, punished drinking and fear induced USVs in rats and marble-burying behaviour in mice.	Vestipitant is currently in phase II clinical trials in combination with paroxetine for social anxiety disorder.	(Ebner and Singewald, 2006; Brocco et al., 2008; Ebner et al., 2009) (http://www.clinicaltrials,gov)
Translocator protein (18 kD)	Neurosteroid production enhancement	XBD173	Anxiolytic effects in the rat social interaction test and elevated plus maze. Inhibits sodium lactate and CCK-4 induced panic in rats.	Inhibits CCK-4 induced anxiety in healthy human volunteers.	(Rupprecht et al., 2009; 2010)
Other neurotransmitter systems
MCH1	Antagonists	SNAP −7941, TPI 1361–17	Increases social interaction in the social interaction test. TPI 1361–17 has an anxiolytic effect in the EPM and light–dark box.		(Doggrell, 2003; Shimazaki et al., 2006; Lee et al., 2010)