Clozapine is the golden standard for treatment-resistant schizophrenia (TRS), and its main metabolite N-desmethylclozapine (NDMC) exhibits robust M1 muscarinic acetylcholine receptor agonistic activity, supporting the M1-hypothesis for clozapine's unique actions. To validate this hypothesis, we aimed to develop clozapine-like compounds with the following profile: (i) robust M1 agonism, (ii) clozapine-like binding affinity toward various GPCRs, (iii) reduced reactive metabolite formation, (iv) no or weak M3 agonism, and (v) high brain permeability. Through structure-activity relationship (SAR) studies based on lead compound 4, we identified compound 8 (2-fluoro-8-methyl-11-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5H-dibenzo[b,e][1,4]diazepine). Compound 8 showed strong M1 agonistic activity (EC50: 0.31 μM, Emax: 75 ± 3%) without M3 agonism, clozapine-like binding affinity toward dopamine D1/D2, 5-HT2A, and other GPCRs, significantly lower reactive metabolite formation compared to clozapine, and good brain penetration (brain/plasma ratio: 5.2) in mice. These results indicate that compound 8 is a promising candidate to verify the M1-hypothesis of clozapine and a unique muscarinic acetylcholine-serotonin-dopamine modulator for TRS.