A model of the muscarinic m1 receptor has been constructed on the basis of the putative three-dimensional structural similarity between bacteriorhodopsin and G-protein coupled receptors. The homology-based m1 receptor model takes into account hydrophobicity and conserved amino acids and information from site-directed mutagenesis studies and from hydropathy plots. The resulting model was used in conjunction with an indirect model which describes a proposed active agonist conformation of acetylcholine and a number of related compounds. A receptor-excluded volume was constructed by superimposing these muscarinic agonists and calculating their combined van der Waals volume. The resulting m1 receptor excluded volume was used to define the agonist binding site, which consists of nine amino acids and which binds agonists primarily through interaction with Asp105 (ionic interaction). Thr192 and Asn382 (hydrogen bonds). The model is flexible since the conformation of the nine amino acids may change in response to the agonist structure. The combination of indirect and homology-based approaches is particularly attractive since it utilizes more experimental data than a purely homology-based model and since a binding-site model might be more realistic and general in terms of applicability than indirect models. Docking of the ligands was performed by optimizing attractive interactions and minimizing repulsive interactions. In addition to the agonists used to define the binding site, structurally different agonists are also accommodated by the binding-site model. Furthermore, the m1 receptor binding-site model is able to reproduce experimentally determined stereoselectivities.