Figure 9.

In pursuit of a better xanomeline. Shown are structures of xanomeline (40) and subsequent M₁ allosteric agonists 41–44, which demonstrated that all were bitopic with receptor reserve-dependent pharmacology (e.g., brain region-specific activity) and thus not tractable as a therapeutic approach. PAMs of either M₁ (45 and 46) or M₄ (47 or 48) have emerged as important in vivo tools to demonstrate that this mode of pharmacology is superior to allosteric agonism with true mAChR selectivity.