A series of β-naltrexamine and 0-oxymorphamine derivatives that contain ionizable moieties coupled to the 6β-amino group were synthesized in an effort to develop antagonists and agonists that have negligible access into the central nervous system (CNS). Among the β-naltrexamine derivatives 1–7, all displayed partial agonism on the guinea pig ileal longitudinal muscle preparation except for aspartyl derivative 6, which was a full agonist with activity in the range of morphine. The β-oxymorphamine derivatives 8–12 were all full agonists with potencies ranging from 1.5 to 6.1 times that of morphine. Among the compounds evaluated in mice for antinociceptive or opioid antagonist activities, aspartyl derivative 6 possessed the greatest difference between peripheral (po or iv) and icv equiactive antagonist doses. Compared to naltrexone, 6 was >100 times more potent by the icv route, but 6000–10000 times less potent when administered po or icv. The present study suggests that zwitterionic groups are highly effective in preventing penetration of ligands into the CNS. Such ligands may be useful pharmacologic tools for investigation of peripheral opioid mechanisms. Moreover, they could find clinical applications when the central actions are unwanted.