The search for selective kappa opioid receptor (κOR) agonists with an improved safety profile is an area of interest in opioid research. In this work, a series of <i>m</i>-substituted analogs were designed, synthesized, and assayed, resulting in the identification of compound <b>6c</b> (<b>SLL-1206</b>) as a κOR agonist with single-digit nanomolar activities. The subtype selectivity of compound <b>6c</b> appeared to be a consequence of an enormous decrease in the affinity for μOR and δOR, rather than a significant increase in the affinity for κOR, which was not the case for <b>SLL-039</b>, another selective and potent κOR agonist identified in our previous work. Besides reduced central nervous system effects, <b>SLL-1206</b> exhibited substantially improved physicochemical and pharmacokinetic properties compared with <b>SLL-039</b>, with increases of over 20-fold in aqueous solubility and approximately 40-fold in oral bioavailability in rats.