Recent medicinal chemistry studies have led to the idea that muscarinic ligands of differing efficacy employ distinctly different pharmacophores when interacting with their specific receptor. Although the primary recognition element, the cationic head group, remains constant for all ligands, two H-bonding interactions are used selectively to stabilize agonist binding. In contrast, antagonists rely predominantly upon hydrophobic binding in the vicinity of the acetylmethyl group present in the endogenous transmitter. These ideas have been evaluated in the context of a three-dimensional model of the muscarinic receptor derived originally from bacteriorhodopsin. Together these studies have allowed speculations to be made regarding the sequence of events which lead to coupling to G-protein. Although an Asp residue on helix III of the seven-helical model is known to be involved as the primary recognition site for all ligands, a second, more deeply buried Asp on helix II is suggested to represent the ultimate agonist-binding site from which receptor activation is triggered. Similar arguments are also applied to homologous receptor systems, in particular the beta-adrenergic receptor.