In a dataset that we previously provided for SAMPL7, we used CDs monosubstituted at the secondary face with large substituents of varied polarity (e.g., a steroid, a zwitterionic amino acid, and a sugar). However, these substitutions led to only modest shifts in affinity. We have since found that heptakis substitution of specific hydroxyls of βCD with even small substituents can modulate binding more substantially. Accordingly, we generated the current dataset by testing our selected phenothiazines against native βCD and derivatives modified by heptakis methylation at the three classes of hydroxyls: per-6-O-methyl, per-2,6-di-O-methyl, and per-2,3,6-tri-O-methyl (Figure ). Combining these with the phenothiazine family of guests results in a dataset that systematically probes chemical variations of both the phenothiazine guests and the CD hosts, producing trends in binding thermodynamics that make for a systematic and informative SAMPL challenge. We used a combination of isothermal titration calorimetry (ITC) and NMR spectroscopy to explore how three patterns of βCD methylation influence the binding of five phenothiazine drugs (Table ). The resulting data were used in the SAMPL9 blinded binding affinity-prediction challenge (), as reflected in the accompanying articles. Note that our core purpose is not to provide a theoretical or computational analysis of the present experimental results, but rather to provide the data needed to support the SAMPL9 studies, while also highlighting features of interest. Because the drugs studied here are in clinical use for various chiefly psychiatric indications and carry significant toxicity at high doses, the present data also raise the possibility of developing CD derivatives with higher affinities for these drugs, for possible use as overdose reversal agents, much as sugammadex is used to reverse paralysis by rocuronium and vecuronium. Table . Names, abbreviations, and structures of the five phenothiazine drugs studied here, along with computational estimates of selected chemical properties from Drugbank . Protonation states shown are those expected at pH 7. 3 MATERIALS AND METHODS