Fig. 1.

Influences of agonist concentration, modulator affinity, and cooperativity on allosteric modulator potency. A and B, simulations of the effects of different agonist concentrations on the potencies of a negative allosteric modulator (A) and a positive allosteric modulator (B). EC100**, agonist concentration 30-fold in excess of that required to elicit a maximal response. C and D, literature findings on mGlu₅ NAM potency and affinity estimates (C) and mGlu₅ PAM potency and affinity estimates (D) (Huang et al., 2004; Poon et al., 2004; Roppe et al., 2004; Chua et al., 2005; Tehrani et al., 2005; de Paulis et al., 2006; Kulkarni et al., 2006, 2009; Jaeschke et al., 2007; Milbank et al., 2007; Liu et al., 2008; Vanejevs et al., 2008; Felts et al., 2009, 2010; Galambos et al., 2010; Rodriguez et al., 2010; Wágner et al., 2010; Zhang et al., 2010; Alagille et al., 2011; Gilbert et al., 2011; Lindemann et al., 2011; Sams et al., 2011; Weiss et al., 2011; Zou et al., 2011; Mueller et al., 2012). Dashed lines, unity; dotted lines, potency and affinity within 3-fold of each other; solid lines, 10-fold difference.