Designer receptors exclusively activated by designer drugs (DREADDs) are chemogenetically modified muscarinic acetylcholine receptors (mAChRs) that have minimal responsiveness to acetylcholine (ACh) but are potently and efficaciously activated by an otherwise inert synthetic ligand, clozapine-N-oxide (CNO). DREADDs have been used as tools for selectively modulating signal transduction pathways in vitro and in vivo. Recent comprehensive studies have validated how the pharmacology of a CNO-bound DREADD mirrors that of an ACh-bound wild-type (WT) mAChR. However, nothing is known about whether this equivalence extends to the allosteric modulation of DREADDs by small molecules. To address this, we investigated the actions at an M1 DREADD of benzyl quinolone carboxylic acid (BQCA), a positive allosteric modulator of ACh binding and function that is known to behave according to a simple twostate mechanism at the WT receptor. We found that allosteric modulation of the CNO-bound DREADD receptor is not equivalent to the corresponding modulation of the AChbound WT receptor. We also found that BQCA engenders stimulus bias at the M1 DREADD, having differential types of cooperativity depending on the signaling pathway. Furthermore, the modulation of ACh itself by BQCA at the DREADD is not compatible with the two-state model that we previously applied to the M1 WT receptor.